Substituted imidazo[1,5-a]pyrimidines and their use in the treatment of medical disorders

ABSTRACT

The invention provides substituted imidazo┌1,5-a┐pyrimidines and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease, Parkinson&#39;s disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted imidazo[1,5-a]pyrimidine compounds described herein include substituted 2,4-dimethyl-N-phenylimidazo[1,5-a]pyrimidine-8-carbox-amide compounds and variants thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application Ser. No. 62/076,070, filed Nov. 6, 2014, the contentsof which are hereby incorporated by reference.

FIELD OF THE INVENTION

The invention provides substituted imidazo[1,5-a]pyrimidines and relatedorganic compounds, compositions containing such compounds, medical kits,and methods for using such compounds and compositions to treat medicaldisorders in a patient.

BACKGROUND

Gaucher disease is a genetic disorder associated with a deficiency ofthe lysosomal enzyme, glucocerebrosidase. Gaucher disease has beenreported to have an incidence of approximately 1 in 20,000 live birthsin the general population, and it is a common lysosomal storagedisorder. Current treatments for patients suffering from this diseaseinclude enzyme replacement therapy, which tends to be expensive,analgesics for bone pain relief, and medical procedures such as bloodand platelet transfusions, splenectomy, and joint replacement forpatients who experience bone erosion. However, new treatment options areneeded having improved efficacy across a broader range of patientsand/or reduced adverse side effects.

Mutations in the gene encoding glucocerebrosidase are also a risk factorfor

Parkinson's disease and diffuse Lewy Body Disease. Parkinson's diseaseis a degenerative disorder of the central nervous system associated withdeath of dopamine-containing cells in a region of the midbrain.Parkinson's disease afflicts millions of people, and the incidence ofthe disease increases with age. Treatment of Parkinson's diseasefrequently involves use of levodopa and dopamine agonists. However,these drugs can produce significant side effects such as hallucinations,insomnia, nausea, and constipation. Further, patients often developtolerance to these drugs such that the drugs become ineffective attreating the symptoms of the disease, while sometimes also producing amovement disorder side effect called dyskinesia. Diffuse Lewy Bodydisease is a dementia that is sometimes confused with Alzheimer'sdisease.

Accordingly, the need exists for new therapeutic agents for treatingGaucher disease, Parkinson's disease, and related medical disorders. Thepresent invention addresses this need and provides other relatedadvantages.

SUMMARY

The invention provides substituted imidazo[1,5-a]pyrimidines and relatedorganic compounds, compositions containing such compounds, medical kits,and methods for using such compounds and compositions to treat medicaldisorders, e.g., Gaucher disease, Parkinson's disease, Lewy bodydisease, dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycystic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis, andmultiple myeloma, in a patient. Various aspects and embodiments of theinvention are described in further detail below.

Accordingly, one aspect of the invention provides a family ofsubstituted imidazo[1,5-a]pyrimidines and related organic compoundsembraced by Formula I that may be used in the methods, compositions andkits described herein, wherein Formula I is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a substitutedimidazo[1,5-a]pyrimidine or related organic compound described herein,such as a compound of Formula I.

Another aspect of the invention provides a method of treating adisorder, e.g.,

Gaucher disease, Parkinson's disease, Lewy body disease, dementia,multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, ananxiety disorder, major depression, polycystic kidney disease, type 2diabetes, open angle glaucoma, multiple sclerosis, and multiple myeloma,in a patient. The method comprises administering to a patient in needthereof a therapeutically effective amount of a substitutedimidazo[1,5-a]pyrimidine or related organic compound described herein,such as a compound of Formula I, to treat the disorder, e.g., Gaucherdisease, Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycystic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, or multiple myeloma.

DETAILED DESCRIPTION

The invention provides substituted imidazo[1,5-a]pyrimidines and relatedorganic compounds, compositions containing such compounds, medical kits,and methods for using such compounds and compositions to treat medicaldisorders in a patient. The practice of the present invention employs,unless otherwise indicated, conventional techniques of organicchemistry, pharmacology, cell biology, and biochemistry. Such techniquesare explained in the literature, such as in “Comprehensive OrganicSynthesis” (B. M. Trost & I. Fleming, eds., 1991-1992); “Currentprotocols in molecular biology” (F. M. Ausubel et al., eds., 1987, andperiodic updates); and “Current protocols in immunology” (J. E. Coliganet al., eds., 1991), each of which is herein incorporated by referencein its entirety. Various aspects of the invention are set forth below insections; however, aspects of the invention described in one particularsection are not to be limited to any particular section.

I. DEFINITIONS

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁—C₁₂alkyl,C₁—C₁₀alkyl, and C₁—C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1 -pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3 -methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “alkylene” refers to a diradical of an alkyl group. Anexemplary alkylene group is —CH₂CH₂—.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,and the like.

The term “heteroalkyl” as used herein refers to an “alkyl” group inwhich at least one carbon atom has been replaced with a heteroatom(e.g., an O, N, or S atom). The heteroalkyl may be, for example, an—O—C₁—C₁₀alkyl group, an —C₁—C₆alkylene-O—C₁—C₆alkyl group, or aC₁—C₆alkylene-OH group. In certain embodiments, the “heteroalkyl” may be2-8 membered heteroalkyl, indicating that the heteroalkyl contains from2 to 8 atoms selected from the group consisting of carbon, oxygen,nitrogen, and sulfur. In yet other embodiments, the heteroalkyl may be a2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (whichmay contain for example 1 or 2 heteroatoms selected from the groupoxygen and nitrogen). One type of heteroalkyl group is an “alkoxyl”group.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂—C₁₂alkenyl, C₂—C₁₀alkenyl, and C₂—C₆alkenyl,respectively. Exemplary alkenyl groups include vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂—C₁₂alkynyl, C₂—C₁₀alkynyl, and C₂—C₆alkynyl,respectively. Exemplary alkynyl groups include ethynyl, prop-1-yn-1-yl,and but-1-yn-1-yl.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8,or 4-6 carbons, referred to herein, e.g., as “C₄₋₈cycloalkyl,” derivedfrom a cycloalkane. Exemplary cycloalkyl groups include, but are notlimited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.Unless specified otherwise, cycloalkyl groups are optionally substitutedat one or more ring positions with, for example, alkanoyl, alkoxy,alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl,arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato,sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkylgroups can be fused to other cycloalkyl, aryl, or heterocyclyl groups.In certain embodiments, the cycloalkyl group is not substituted, i.e.,it is unsubstituted.

The term “cycloalkylene” refers to a diradical of an cycloalkyl group.An exemplary cycloalkylene group is

The term “cycloalkenyl” as used herein refers to a monovalentunsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl)hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing onecarbon-carbon double bond, referred to herein, e.g., as“C₄₋₈cycloalkenyl,” derived from a cycloalkane. Exemplary cycloalkenylgroups include, but are not limited to, cyclohexenes, cyclopentenes, andcyclobutenes. Unless specified otherwise, cycloalkenyl groups areoptionally substituted at one or more ring positions with, for example,alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl,arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato,sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certainembodiments, the cycloalkenyl group is not substituted, i.e., it isunsubstituted.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. The term “aryl” includes polycyclic ring systems havingtwo or more carbocyclic rings in which two or more carbons are common totwo adjoining rings (the rings are “fused rings”) wherein at least oneof the rings is aromatic and, e.g., the other ring(s) may becycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unlessspecified otherwise, the aromatic ring may be substituted at one or morering positions with, for example, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl,carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide,ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties,—CF₃, —CN, or the like. In certain embodiments, the aromatic ring issubstituted at one or more ring positions with halogen, alkyl, hydroxyl,or alkoxyl. In certain other embodiments, the aromatic ring is notsubstituted, i.e., it is unsubstituted. In certain embodiments, the arylgroup is a 6-10 membered ring structure.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “bicyclic carbocyclyl that is partially unsaturated” refers toa bicyclic carbocyclic group containing at least one double bond betweenring atoms and at least one ring in the bicyclic carbocyclic group isnot aromatic. Representative examples of a bicyclic carbocyclyl that ispartially unsaturated include, for example:

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized andrefer to saturated, partially unsaturated, or aromatic 3- to 10-memberedring structures, alternatively 3- to 7-membered rings, whose ringstructures include one to four heteroatoms, such as nitrogen, oxygen,and sulfur. The number of ring atoms in the heterocyclyl group can bespecified using C_(x)—C_(x) nomenclature where x is an integerspecifying the number of ring atoms. For example, a C₃—C₇heterocyclylgroup refers to a saturated or partially unsaturated 3- to 7-memberedring structure containing one to four heteroatoms, such as nitrogen,oxygen, and sulfur. The designation “C₃—C₇” indicates that theheterocyclic ring contains a total of from 3 to 7 ring atoms, inclusiveof any heteroatoms that occupy a ring atom position. One example of aC₃heterocyclyl is aziridinyl. Heterocycles may also be mono-, bi-, orother multi-cyclic ring systems. A heterocycle may be fused to one ormore aryl, partially unsaturated, or saturated rings. Heterocyclylgroups include, for example, biotinyl, chromenyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl,homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl,isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl,piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl,thiopyranyl, xanthenyl, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. Unless specifiedotherwise, the heterocyclic ring is optionally substituted at one ormore positions with substituents such as alkanoyl, alkoxy, alkyl,alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido,carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,nitro, oxo, phosphate, phosphonato, phosphinato, sulfate, sulfide,sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, theheterocyclyl group is not substituted, i.e., it is unsubstituted.

The term “bicyclic heterocyclyl” refers to a heterocyclyl group thatcontains two rings that are fused together. Representative examples of abicyclic heterocyclyl include, for example:

In certain embodiments, the bicyclic heterocyclyl is an carbocyclic ringfused to partially unsaturated heterocyclic ring, that together form abicyclic ring structure having 8-10 ring atoms (e.g., where there are 1,2, 3, or 4 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur).

The term “heterocycloalkyl” is art-recognized and refers to a saturatedheterocyclyl group as defined above. In certain embodiments, the“heterocycloalkyl” is a 3- to 10-membered ring structures, alternativelya 3- to 7-membered rings, whose ring structures include one to fourheteroatoms, such as nitrogen, oxygen, and sulfur.

The term “heterocycloalkylene” refers to a diradical of aheterocycloalkyl group. An exemplary heterocycloalkylene group is

The heterocycloalkylene may contain, for example, 3-6 ring atom (i.e., a3-6 membered heterocycloalkylene). In certain embodiments, theheterocycloalkylene is a 3-6 membered heterocycloalkylene containing 1,2, or 3 three heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl,alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Theterm “heteroaryl” also includes polycyclic ring systems having two ormore rings in which two or more carbons are common to two adjoiningrings (the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, and/or aryls. In certain embodiments, theheteroaryl ring is substituted at one or more ring positions withhalogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, theheteroaryl ring is not substituted, i.e., it is unsubstituted. Incertain embodiments, the heteroaryl group is a 5- to 10-membered ringstructure, alternatively a 5- to 6-membered ring structure, whose ringstructure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen,and sulfur.

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety represented by thegeneral formula —N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independentlyrepresent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl,aralkyl, or —(CH₂)_(m)—R⁶¹; or R⁵⁰ and R⁵¹, taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ eachindependently represent hydrogen, alkyl, alkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R₆₁,where m and R₆₁ are described above.

The term “carbamate” as used herein refers to a radical of the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i)—, or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, orsulfonamide. Exemplary carbamates include arylcarbamates and heteroarylcarbamates, e.g., wherein at least one of R_(g), R_(h) and R_(i) areindependently aryl or heteroaryl, such as phenyl and pyridinyl.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “carboxamido” as used herein refers to the radical —C(O)NRR′,where R and R′ may be the same or different. R and R′ may beindependently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl,heteroaryl, or heterocyclyl.

The term “carboxy” as used herein refers to the radical —COOH or itscorresponding salts, e.g. —COONa, etc.

The term “amide” or “amido” as used herein refers to a radical of theform —R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, —C(O)NR_(b)R_(c), or—C(O)NH₂, wherein R_(a), R_(b) and R_(c) are each independently alkoxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, or nitro. The amide can beattached to another group through the carbon, the nitrogen, R_(b),R_(c), or R_(a). The amide also may be cyclic, for example R_(b) andR_(c), R_(a) and R_(b), or R_(a) and R_(c) may be joined to form a 3- to12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-memberedring.

The term “amidino” as used herein refers to a radical of the form—C(═NR)NR′R″ where R, R′, and R″ are each independently alkyl, alkenyl,alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, hydroxyl, ketone, or nitro.

The term “alkanoyl” as used herein refers to a radical —O—CO-alkyl.

The term “oxo” is art-recognized and refers to a “═O” substituent. Forexample, a cyclopentane susbsituted with an oxo group is cyclopentanone.

The term “sulfonamide” or “sulfonamido” as used herein refers to aradical having the structure —N(R_(r))—S(O)₂—R_(s)— or—S(O)₂—N(R_(r))R_(s), where R_(r), and R_(s) can be, for example,hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplarysulfonamides include alkylsulfonamides (e.g., where R_(s) is alkyl),arylsulfonamides (e.g., where R_(s) is aryl), cycloalkyl sulfonamides(e.g., where R_(s) is cycloalkyl), and heterocyclyl sulfonamides (e.g.,where R_(s) is heterocyclyl), etc.

The term “sulfonyl” as used herein refers to a radical having thestructure R_(u)SO₂—, where R_(u) can be alkyl, aryl, cycloalkyl, andheterocyclyl, e.g., alkylsulfonyl. The term “alkylsulfonyl” as usedherein refers to an alkyl group attached to a sulfonyl group.

The symbol “

” indicates a point of attachment.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Further, enantiomers can be separated usingsupercritical fluid chromatographic (SFC) techniques described in theliterature. Still further, stereoisomers can be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. The present invention encompasses the various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and , ³⁶Cl, respectively.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in, e.g., the Examples herein by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin, Remington'sPharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄alkyl, and thelike.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na^(|), NH₄ ^(|),and NW₄ ^(|) (wherein W is a C₁₋₄alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Abbreviations as used herein includeO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); diisopropylethylamine (DIPEA);dimethylformamide (DMF); methylene chloride (DCM); tert-butoxycarbonyl(Boc);

tetrahydrofuran (THF); trifluoroacetic acid (TFA); N-methylmorpholine(NMM); triethylamine (TEA); Boc anhydride ((Boc)₂O); dimethylsulfoxide(DMSO); diisopropylethylamine (DIEM; flash column chromatography (FCC);and supercritical fluid chromatography (SFC).

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. SUBSTITUTED IMIDAZO[1,5-a]PYRIMIDINES AND RELATED ORGANIC COMPOUNDS

One aspect of the invention provides substitutedimidazo[1,5-a]pyrimidines and related organic compounds. The substitutedimidazo[1,5-a]pyrimidines and related organic compounds are contemplatedto be useful in the methods, compositions, and kits described herein. Incertain embodiments, the substituted imidazo[1,5-a]pyrimidine or relatedorganic compound is a compound embraced by Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,        —(C₁₋₄alkylene)-(C₁₋₄alkoxyl), cyclopropyl, cyano, chloro, or        fluoro;    -   R² is hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,        cyclopropyl, cyano, chloro, or fluoro;    -   R³ represents independently for each occurrence hydrogen or        C₁₋₄alkyl;    -   R⁴ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, or —C(O)R³;    -   X¹ is one of the following:        -   (a) a carbonyl-containing linker selected from —C(O)N(H)-ψ,            —C(O)N(H)(C₁₋₆alkylene)-ψ, and —C(O)-(3-6 membered            heterocycloalkylene containing at least one ring —N(H)—            group)ψ; where ψ is a bond to A¹; or        -   (b) an amine-containing linker selected from            —(C₁₋₄alkylene)-N(H)-ψ and 13            (C₁₋₄alkylene)-N(H)-(C₁₋₄alkylene)-ψ;    -   A¹ is a cyclic group selected from:        -   C₃₋₁₀ cycloalkyl, phenyl, or 5-6 membered heteroaryl, each            of which is substituted by 1 or 2 occurrences of Y¹ and 0,            1, 2, or 3 occurrences of Y²; and        -   a bicyclic carbocyclyl that is partially unsaturated or a            mono-cyclic or bicyclic heterocyclyl, each of which is            substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or            3 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl,            C₃₋₇-cycloalkyl, —O—C₃₋₇cycloalkyl, —O-(3-6 membered            heterocyclyl), —O-(6-10 membered aryl), or —O—(C₂₋₆alkynyl);        -   C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,            —C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆alkenyl; or        -   halogen or cyano;    -   Y² represents, independently for each occurrence, deuterium,        C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl,        C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, azido,        —N(R³)₂,—(C₁₋₆alkylene)-(5-6 membered heterocyclyl),        —(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl-substituted        C₃₋₆cycloalkyl; and    -   n is 1, 2, or 3.

Definitions of the variables in Formula I above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)-ψ, A¹ is phenyl or 5-6 memberedheteroaryl, and Y¹ is 2-8 membered heteroalkyl.

Accordingly, in certain embodiments, R¹ represents independently foreach occurrence C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, cyclopropyl,cyano, chloro, or fluoro. In certain embodiments, R¹ representsindependently for each occurrence C₁₋₄alkyl, C₁₋₄haloalkyl, cyclopropyl,cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. Incertain embodiments, the R¹ groups are located at the 2 and 4 positionsof the imidazo[1,5-a]pyrimidinyl.

In certain embodiments, n is 2. In certain other embodiments, n is 1.

In certain embodiments, R¹ represents independently for each occurrencehydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano,chloro, or fluoro; and n is 1.

In certain embodiments, R² is hydrogen. In certain embodiments, R² ismethyl or halogen. In certain embodiments, R² is methyl or halomethyl.In certain embodiments, R² is methyl or cyclopropyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ ishydrogen. In certain embodiments, R⁴ is hydrogen.

In certain embodiments, X¹ is —C(O)N(H)-ψ. In certain embodiments, X¹ is—C(O)N(H)(C₁₋₆alkylene)-ψ or —C(O)-(3-6 membered heterocycloalkylenecontaining at least one ring —N(H)— group)-ψ.

In certain embodiments, A¹ is a cyclic group selected from:

-   -   phenyl, 5-6 membered heteroaryl, or C₃₋₇-cycloalkyl, each of        which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or        3 occurrences of Y²; and    -   a bicyclic carbocyclyl that is partially unsaturated or a        mono-cyclic or bicyclic heterocyclyl, each of which is        substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3        occurrences of Y².

In certain embodiments, A¹ is phenyl or 5-6 membered heteroaryl, each ofwhich is substituted once by Y¹ and 0, 1, or 2 occurrences of Y². Incertain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1occurrences of Y². In certain embodiments, A¹ is a 5-6 memberedheteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is pyridinyl substituted once by Y¹ and 0-1 occurrencesof Y².

In certain embodiments, A¹ is C₅₋₁₀ cycloalkyl substituted once by Y¹and 0-1 occurrences of Y². In certain embodiments, A¹ is C₃₋₇-cycloalkylsubstituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is a cyclopentyl or cyclohexyl, each of which issubstituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is a bicyclic carbocyclyl that is partiallyunsaturated or a bicyclic heterocyclyl, each of which is substituted by0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certainembodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturatedor a bicyclic heterocyclyl, each of which is substituted by 0 or 1occurrence of Y² selected from the group consisting of C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆alkoxyl.

In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,C₁₋₆alkoxyl, or cyano. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,or C₁₋₆alkoxyl.

In certain embodiments, any occurrence of Y² is independently C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, or hydroxyl. In certainembodiments, any occurrence of Y² is independently C₁₋₃alkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a6-10 membered aryl or a 3-10 membered heterocyclyl. In certainembodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl,furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl. In certain embodiments, R¹ is —OCH₂CH₂OCH₂CH₂.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O-butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl). In certain embodiments, Y¹ is—CH₂—O-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl,thiazolinyl, or triazolinyl, each of which is substituted by one or twosubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇-cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₇-cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl,C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certain embodiments,Y¹ is a 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆alkoxyl.

In certain embodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, or thiazolyl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl, each of which is substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl,C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl. Incertain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, eachof which is substituted by one or two substituents independentlyselected from the group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl,halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano,—N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆alkynyl, —C≡C(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered heteroaryl),or C₂₋₆alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl. In certainembodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-OR⁴. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-O—(C₁₋₂alkyl). In certain embodiments, Y¹ is—C≡C—CH₂—O—CH₃.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments. For example, the inventioncontemplates a compound of Formula I wherein X¹ is —C(O)N(H)-ψ, A¹ isphenyl or 5-6 membered heteroaryl, each of which is substituted once byY¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

In certain embodiments, the compound is a compound of Formula I-1:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano,        chloro, or fluoro;    -   R² is hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,        cyclopropyl, cyano, chloro, or fluoro;    -   R³ represents independently for each occurrence hydrogen or        C₁₋₄alkyl;    -   R⁴ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, or —C(O)R³;    -   X¹ is one of the following:        -   (a) a carbonyl-containing linker selected from —C(O)N(H)-ψ,            —C(O)N(H)(C₁₋₆alkylene)-ψ, and —C(O)-(3-6 membered            heterocycloalkylene containing at least one ring —N(H)—            group)-ψ; where ψ is a bond to A¹; or        -   (b) an amine-containing linker selected from            —(C₁₋₄alkylene)-N(H)-ψ and            —(C₁₋₄alkylene)-N(H)—(C₁₋₄alkylene)-ψ;    -   A¹ is a cyclic group selected from:        -   phenyl, 5-6 membered heteroaryl, or C₃₋₇-cycloalkyl, each of            which is substituted by 1 or 2 occurrences of Y¹ and 0, 1,            2, or 3 occurrences of Y²; and        -   a bicyclic carbocyclyl that is partially unsaturated or a            mono-cyclic or bicyclic heterocyclyl, each of which is            substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or            3 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl,            C₃₋₇-cycloalkyl, —O-(3-6membered heterocyclyl), —O-(6-10            membered aryl), or —O—(C₂₋₆alkynyl); or        -   C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,            —C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆alkyl,        C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,        hydroxyl, C₁₋₆alkoxyl, cyano, azido, —N(R³)₂,        —(C₁₋₆alkylene)-(5-6 membered heterocyclyl),        —(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl-substituted        C₃₋₆cycloalkyl; and    -   n is 1, 2, or 3.

Definitions of the variables in Formula I-1 above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)-ψ, A¹ is phenyl or 5-6 memberedheteroaryl, and Y¹ is 2-8 membered heteroalkyl.

Accordingly, in certain embodiments, R¹ represents independently foreach occurrence C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, cyclopropyl,cyano, chloro, or fluoro. In certain embodiments, R¹ representsindependently for each occurrence C₁₋₄alkyl, C₁₋₄haloalkyl, cyclopropyl,cyano, chloro, or fluoro. In certain embodiments, R¹ is methyl. Incertain embodiments, the R¹ groups are located at the 2 and 4 positionsof the imidazo[1,5-a]pyrimidinyl.

In certain embodiments, n is 2. In certain other embodiments, n is 1.

In certain embodiments, R¹ represents independently for each occurrencehydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano,chloro, or fluoro; and n is 1.

In certain embodiments, R² is hydrogen. In certain embodiments, R² ismethyl or halogen. In certain embodiments, R² is methyl or halomethyl.In certain embodiments, R² is methyl or cyclopropyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl. In certain embodiments, R³ ishydrogen. In certain embodiments, R⁴ is hydrogen.

In certain embodiments, X¹ is —C(O)N(H)-ψ. In certain embodiments, X¹ is—C(O)N(H)(C₁₋₆alkylene)-ψ or —C(O)-(3-6 membered heterocycloalkylenecontaining at least one ring —N(H)— group)-ψ.

In certain embodiments, A¹ is a cyclic group selected from:

-   -   phenyl, 5-6 membered heteroaryl, or C₃₋₇-cycloalkyl, each of        which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or        3 occurrences of Y²; and    -   a bicyclic carbocyclyl that is partially unsaturated or a        mono-cyclic or bicyclic heterocyclyl, each of which is        substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3        occurrences of Y².

In certain embodiments, A¹ is phenyl or 5-6 membered heteroaryl, each ofwhich is substituted once by Y¹ and 0, 1, or 2 occurrences of Y². Incertain embodiments, A¹ is phenyl substituted once by Y¹ and 0-1occurrences of Y². In certain embodiments, A¹ is a 5-6 memberedheteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is pyridinyl substituted once by Y¹ and 0-1 occurrencesof Y².

In certain embodiments, A¹ is C₅₋₁₀cycloalkyl substituted once by Y¹ and0-1 occurrences of Y². In certain embodiments, A¹ is C₃₋₇-cycloalkylsubstituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is a cyclopentyl or cyclohexyl, each of which issubstituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is a bicyclic carbocyclyl that is partiallyunsaturated or a bicyclic heterocyclyl, each of which is substituted by0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certainembodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturatedor a bicyclic heterocyclyl, each of which is substituted by 0 or 1occurrence of Y² selected from the group consisting of C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆alkoxyl.

In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,C₁₋₆alkoxyl, or cyano. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,or C₁₋₆ alkoxyl.

In certain embodiments, any occurrence of Y² is independently C₁₋₆alkyl,C₃₋₆ cycloalkyl, halogen, C₁₋₆haloalkyl, or hydroxyl. In certainembodiments, any occurrence of Y² is independently C₁₋₃alkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a6-10 membered aryl or a 3-10 membered heterocyclyl. In certainembodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl,furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl. In certain embodiments, R¹ is —OCH₂CH₂OCH₂CH₂.

In certain embodiments, Y¹ is —O—(C₁₋₂alkyl). In certain embodiments, Y¹is —O-butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl). In certain embodiments, Y¹ is—CH₂—O-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl,thiazolinyl, or triazolinyl, each of which is substituted by one or twosubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇-cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is a 5-membered heteroaryl. In certain embodiments, Y¹is a 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₇-cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl,C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certain embodiments,Y¹ is a 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆alkoxyl.

In certain embodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, or thiazolyl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl, each of which is substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆alkyl,C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl,C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl. Incertain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, eachof which is substituted by one or two substituents independentlyselected from the group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl,halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano,—N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆ alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 memberedheteroaryl), or C₂₋₆alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl.In certain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-OR⁴. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-O—(C₁₋₂alkyl). In certain embodiments, Y¹ is—C≡C—CH₂—O—CH₃.

The description above describes multiple embodiments relating tocompounds of Formula I-1. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I wherein X¹ is—C(O)N(H)-ψ, A¹ is phenyl or 5-6 membered heteroaryl, each of which issubstituted once by Y¹ and 0, 1, or 2 occurrences of Y², and Y¹ is 2-8membered heteroalkyl.

In certain embodiments, the compound is a compound of Formula I-la:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ represents independently for each occurrence C₁₋₄alkyl;    -   R² and R³ each represent independently for each occurrence        hydrogen or C₁₋₄alkyl;    -   R⁴ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, or —C(O)R³;    -   X¹ is one of the following:        -   (a) a carbonyl-containing linker selected from —C(O)N(H)-ψ,            —C(O)N(H)(C₁₋₆alkylene)-ψ, and —C(O)-(3-6 membered            heterocycloalkylene containing at least one ring —N(H)—            group)-ψ; where ψ is a bond to A¹; or        -   (b) an amine-containing linker selected from            —(C₁₋₄alkylene)-N(H)-ψ and            —(C₁₋₄alkylene)-N(H)—(C₁₋₄alkylene)-ψ;    -   A¹ is a cyclic group selected from:        -   phenyl, 5-6 membered heteroaryl, or C₃₋₇-cycloalkyl, each of            which is substituted by 1 or 2 occurrences of Y¹ and 0, 1,            2, or 3 occurrences of Y²; and        -   a bicyclic carbocyclyl that is partially unsaturated or a            mono-cyclic or bicyclic heterocyclyl, each of which is            substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or            3 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl, —O-(3-6            membered heterocyclyl), —O-(6-10 membered aryl), or            —O—(C₂₋₆alkynyl); or        -   C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,            —C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆alkyl,        C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,        hydroxyl, C₁₋₆alkoxyl, cyano, azido, —N(R³)₂,        —(C₁₋₆alkylene)-(5-6 membered heterocyclyl),        —(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl⁻substituted C₃₋₆        cycloalkyl; and    -   n is 1, 2, or 3.

Definitions of the variables in Formula I-1a above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)-ψ, A¹ is phenyl or 5-6 memberedheteroaryl, and Y¹ is 2-8 membered heteroalkyl.

In certain embodiments, the compound is a compound of Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is independently methyl, cyclopropyl, isopropyl, or        —(C₁₋₄alkylene)-(C₁₋₄alkoxyl);    -   R² is hydrogen;    -   R³ and R⁴ each represent independently for each occurrence        hydrogen or C₁₋₄alkyl;    -   A¹ is a cyclic group selected from:        -   C₃₋₁₀ cycloalkyl, phenyl, or 5-6 membered heteroaryl, each            of which is substituted by 1 occurrence of Y¹ and 0, 1, or 2            occurrences of Y²; and        -   a bicyclic carbocyclyl that is partially unsaturated or a            bicyclic heterocyclyl, each of which is substituted by 0 or            1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl, —O-(3-6            membered heterocyclyl), —O-(6-10 membered aryl), or            —O—(C₂₋₆alkynyl); or        -   C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,            —C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆alkyl,        C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,        hydroxyl, C₁₋₆alkoxyl, cyano, azido, —N(R³)₂,        —(C₁₋₆alkylene)-(5-6 membered heterocyclyl),        —(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl-substituted        C₃₋₆cycloalkyl.

Definitions of the variables in Formula I-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where A¹ is phenyl or 5-6 membered heteroaryl, each of which issubstituted once by Y¹, where Y¹ is a 2-8 membered heteroalkyl.

Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 memberedheteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences ofY².

In certain embodiments, any occurrence of Y² is independently C₁₋₃alkyl,halogen, or C₁₋₃haloalkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is —O—(C₁₋₇alkyl). In certain embodiments, Y¹ is—O-butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl).

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, —O-(3-6 membered heterocyclyl), —O-(6-10 membered aryl),or —O—(C₂₋₆alkynyl). In certain embodiments, Y¹ is a 3-10 memberedheterocyclyl. In certain embodiments, Y¹ is a 3-10 membered heterocyclylselected from the group consisting of a 5-6 membered heteroaryl and a5-6 membered heterocycloalkyl.

In certain embodiments, Y¹ is a 5-membered heteroaryl. In certainembodiments, Y¹ is a 5-membered heteroaryl substituted by one or twosubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆ hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certainembodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl,oxazolyl, or thiazolyl. In certain embodiments, Y¹ is furanyl, pyrrolyl,thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of whichis substituted by one or two substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂,amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl. In certainembodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl,isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl,oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted byone or two substituents independently selected from the group consistingof C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered heteroaryl),or C₂₋₆alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl. In certainembodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-OR⁴. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-O—(C₁₋₂alkyl). In certain embodiments, Y¹ is—C≡C—CH₂—O—CH₃.

In certain embodiments, A¹ is a bicyclic carbocyclyl that is partiallyunsaturated or a bicyclic heterocyclyl, each of which is substituted by0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certainembodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturatedor a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2occurrences of Y². In certain embodiments, A¹ is a 2-8 memberedheteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10membered heterocyclyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,or C₁₋₆alkoxyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,C₁₋₆alkoxyl, or cyano.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-A wherein A¹ is phenyl or5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0,1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

In certain embodiments, R¹ is methyl. In certain embodiments, R¹ isfurther selected from halogen and halomethyl, such that R¹ may bemethyl, halogen, or halomethyl.

In certain embodiments, R² is further selected from halogen, such thatR² may be hydrogen or halogen.

In certain embodiments, the compound is a compound of Formula I-A1:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ is independently methyl, cyclopropyl, or isopropyl;    -   R² is hydrogen;    -   R³ and R⁴ each represent independently for each occurrence        hydrogen or C₁₋₄alkyl;    -   A¹ is a cyclic group selected from:        -   phenyl, 5-6 membered heteroaryl, or C₃₋₇-cycloalkyl, each of            which is substituted by 1 occurrence of Y¹ and 0, 1, or 2            occurrences of Y²; and        -   a bicyclic carbocyclyl that is partially unsaturated or a            bicyclic heterocyclyl, each of which is substituted by 0 or            1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl, —O-(3-6            membered heterocyclyl), —O-(6-10 membered aryl), or            —O—(C₂₋₆alkynyl); or        -   C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,            —C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆alkyl,        C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,        hydroxyl, C₁₋₆alkoxyl, cyano, azido, —N(R³)₂,        —(C₁₋₆alkylene)-(5-6 membered heterocyclyl),        —(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl-substituted C₃₋₆        cycloalkyl.

Definitions of the variables in Formula I-A1 above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where A¹ is phenyl or 5-6 membered heteroaryl, each of which issubstituted once by Y¹, where Y¹ is a 2-8 membered heteroalkyl.

Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹and 0-1 occurrences of Y². In certain embodiments, A¹ is a 5-6 memberedheteroaryl substituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is pyridinyl substituted by Y¹ and 0-1 occurrences ofY2.

In certain embodiments, any occurrence of Y² is independently C₁₋₃alkyl,halogen, or C₁₋₃haloalkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is —O—(C₁₋₇alkyl). In certain embodiments, Y¹ is—O-butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl).

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, —O-(3-6 membered heterocyclyl), —O-(6-10 membered aryl),or —O—(C₂₋₆alkynyl). In certain embodiments, Y¹ is a 3-10 memberedheterocyclyl. In certain embodiments, Y¹ is a 3-10 membered heterocyclylselected from the group consisting of a 5-6 membered heteroaryl and a5-6 membered heterocycloalkyl.

In certain embodiments, Y¹ is a 5-membered heteroaryl. In certainembodiments, Y¹ is a 5-membered heteroaryl substituted by one or twosubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certainembodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl,oxazolyl, or thiazolyl. In certain embodiments, Y¹ is furanyl, pyrrolyl,thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of whichis substituted by one or two substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂,amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl. In certainembodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl,isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl,oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted byone or two substituents independently selected from the group consistingof C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered heteroaryl),or C₂₋₆alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl. In certainembodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-OR⁴. In certain embodiments, Y¹ is—C≡C—(C₁₋₆alkylene)-O—(C₁₋₂alkyl). In certain embodiments, Y¹ is—C≡C—CH₂—O—CH₃.

In certain embodiments, A¹ is a bicyclic carbocyclyl that is partiallyunsaturated or a bicyclic heterocyclyl, each of which is substituted by0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certainembodiments, A¹ is a bicyclic carbocyclyl that is partially unsaturatedor a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2occurrences of Y². In certain embodiments, A¹ is a 2-8 memberedheteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10membered heterocyclyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,or C₁₋₆alkoxyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,C₁₋₆alkoxyl, or cyano.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-A wherein A¹ is phenyl or5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0,1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

In certain embodiments, R¹ is methyl. In certain embodiments, R¹ isfurther selected from halogen and halomethyl, such that R¹ may bemethyl, halogen, or halomethyl.

In certain embodiments, R² is further selected from halogen, such thatR² may be hydrogen or halogen.

In certain embodiments, the compound is a compound of Formula I-B:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   A¹ is a cyclic group selected from phenyl, pyridinyl,        cyclopentyl, or cyclohexyl, each of which is substituted by 1        occurrence of Y¹ and 0, 1, or 2 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, a 6 membered aryl, —O-(3-6            membered heterocyclyl), or —O—(C₂₋₆alkynyl); or        -   —C≡C—H, —C≡C—(C₁₋₄alkyl), or —C≡C—(C₁₋₆alkylene)-OR⁴;    -   Y² represents, independently for each occurrence, C₁₋₆alkyl,        C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,        hydroxyl, or C₁₋₆alkoxyl; and    -   R⁴ represents independently for each occurrence hydrogen or        C₁₋₄alkyl.

Definitions of the variables in Formula I-B above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where A¹ is phenyl or pyridinyl, each of which is substitutedonce by Y¹, where Y¹ is 2-8 membered heteroalkyl.

Accordingly, in certain embodiments, A¹ is phenyl substituted once by Y¹and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinylsubstituted by Y¹ and 0-1 occurrences of Y².

In certain embodiments, any occurrence of Y² is independently C₁₋₃alkyl,halogen, or C₁₋₃haloalkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is —O—(C₁₋₇alkyl). In certain embodiments, Y¹ is—O-butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl).

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6 memberedaryl, or —O-(3-6 membered heterocyclyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl. In certain embodiments, Y¹ is a 3-10membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl.

In certain embodiments, Y¹ is a 5-membered heteroaryl. In certainembodiments, Y¹ is a 5-membered heteroaryl substituted by one or twosubstituents independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certainembodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl,oxazolyl, or thiazolyl. In certain embodiments, Y¹ is furanyl, pyrrolyl,thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of whichis substituted by one or two substituents independently selected fromthe group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen,C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, and C₁₋₆alkoxyl.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl. In certainembodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl,isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl,oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted byone or two substituents independently selected from the group consistingof C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

The description above describes multiple embodiments relating tocompounds of Formula I-B. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-B wherein A¹ is phenyl orpyridinyl, each of which is substituted once by Y¹ and 0, 1, or 2occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

In certain embodiments, the compound is a compound of Formula I-C:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   A¹ is a bicyclic carbocyclyl that is partially unsaturated or a        bicyclic heterocyclyl, each of which is substituted by 0 or 1        occurrence of Y¹ and 0, 1, or 2 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, a 6 membered aryl, —O-(3-6            membered heterocyclyl), or —O—(C₂₋₆alkynyl); or        -   —C≡C—H, —C≡C—(C₁₋₄alkyl), or —C≡C—(C₁₋₆alkylene)-OR⁴; and    -   Y² represents, independently for each occurrence, C₁₋₆alkyl,        C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl,        hydroxyl, or C₁₋₆alkoxyl; and    -   R⁴ represents independently for each occurrence hydrogen or        C₁₋₄alkyl.

Definitions of the variables in Formula I-C above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

In certain embodiments, A¹ is a bicyclic carbocyclyl that is partiallyunsaturated or a bicyclic heterocyclyl, each of which is substituted by0 or 1 occurrences of Y².

In certain embodiments, any occurrence of Y² is independently C₁₋₃alkyl,halogen, or C₁₋₃haloalkyl.

In certain other embodiments, the compound is one of the compoundslisted in Table 1 or 2 below or a pharmaceutically acceptable saltthereof.

TABLE 1

Compound No. R^(1-A) R^(1-B) R² X¹ A¹ I-1  methyl methyl H—C(O)N(H)CH₂-ψ

I-2  methyl methyl H —C(O)N(H)CH₂-ψ

I-3  methyl methyl H —C(O)N(H)CH₂-ψ

I-4  methyl methyl H —C(O)N(H)CH₂-ψ

I-5  methyl methyl H —C(O)N(H)CH₂-ψ

I-6  methyl methyl H —C(O)N(H)CH₂-ψ

I-7  methyl methyl H —C(O)N(H)(CH₂)₂-ψ

I-8  methyl methyl H —C(O)N(H)(CH₂)₂-ψ

I-9  methyl methyl H —C(O)N(H)(CH₂)₂-ψ

I-10 methyl methyl H —C(O)N(H)(CH₂)₂-ψ

I-11 methyl methyl H —C(O)N(H)(CH₂)₂-ψ

I-12 methyl methyl H —C(O)N(H)(CH₂)₂-ψ

I-13 methyl methyl H

I-14 methyl methyl H

I-15 methyl methyl H

I-16 methyl methyl H

I-17 methyl methyl H

I-18 methyl methyl H

I-19 methyl methyl H —CH₂N(H)-ψ

I-20 methyl methyl H —CH₂N(H)-ψ

I-21 methyl methyl H —CH₂N(H)-ψ

I-22 methyl methyl H —CH₂N(H)-ψ

I-23 methyl methyl H —CH₂N(H)-ψ

I-24 methyl methyl H —CH₂N(H)-ψ

I-25 methyl methyl H —CH₂N(H)CH₂-ψ

I-26 methyl methyl H —CH₂N(H)CH₂-ψ

I-27 methyl methyl H —CH₂N(H)CH₂-ψ

I-28 methyl methyl H —CH₂N(H)CH₂-ψ

I-29 methyl methyl H —CH₂N(H)CH₂-ψ

I-30 methyl methyl H —CH₂N(H)CH₂-ψ

I-31 methyl methyl methyl —C(O)N(H)CH₂-ψ

I-32 methyl methyl methyl —C(O)N(H)CH₂-ψ

I-33 methyl methyl methyl —C(O)N(H)CH₂-ψ

I-34 methyl methyl methyl —C(O)N(H)CH₂-ψ

I-35 methyl methyl methyl —C(O)N(H)CH₂-ψ

I-36 methyl methyl methyl —C(O)N(H)CH₂-ψ

I-37 methyl H H —C(O)N(H)CH₂-ψ

I-38 methyl H H —C(O)N(H)CH₂-ψ

I-39 methyl H H —C(O)N(H)CH₂-ψ

I-40 methyl H H —C(O)N(H)CH₂-ψ

I-41 methyl H H —C(O)N(H)CH₂-ψ

I-42 methyl H H —C(O)N(H)CH₂-ψ

I-43 methyl H H —C(O)N(H)(CH₂)₂-ψ

I-44 methyl H H —C(O)N(H)(CH₂)₂-ψ

I-45 methyl H H —C(O)N(H)(CH₂)₂-ψ

I-46 methyl H H —C(O)N(H)(CH₂)₂-ψ

I-47 methyl H H —C(O)N(H)(CH₂)₂-ψ

I-48 methyl H H —C(O)N(H)(CH₂)₂-ψ

I-49 H methyl H —C(O)N(H)CH₂-ψ

I-50 H methyl H —C(O)N(H)CH₂-ψ

I-51 H methyl H —C(O)N(H)CH₂-ψ

I-52 H methyl H —C(O)N(H)CH₂-ψ

I-53 H methyl H —C(O)N(H)CH₂-ψ

I-54 H methyl H —C(O)N(H)CH₂-ψ

I-55 H methyl H —C(O)N(H)(CH₂)₂-ψ

I-56 H methyl H —C(O)N(H)(CH₂)₂-ψ

I-57 H methyl H —C(O)N(H)(CH₂)₂-ψ

I-58 H methyl H —C(O)N(H)(CH₂)₂-ψ

I-59 H methyl H —C(O)N(H)(CH₂)₂-ψ

I-60 H methyl H —C(O)N(H)(CH₂)₂-ψ

I-61 methyl —CF₃ H —C(O)N(H)-ψ

I-62 methyl —CF₃ H —C(O)N(H)-ψ

I-63 —CF₃ methyl H —C(O)N(H)-ψ

I-64 —CF₃ methyl H —C(O)N(H)-ψ

I-65 methyl cyclo- propyl H —C(O)N(H)-ψ

I-66 methyl cyclo- propyl H —C(O)N(H)-ψ

I-67 methyl F cyclo- propyl —C(O)N(H)-ψ

I-68 methyl F cyclo- propyl —C(O)N(H)-ψ

I-69 Cl methyl H —C(O)N(H)-ψ

I-70 Cl methyl H —C(O)N(H)CH₂-ψ

I-71 methyl CN H —C(O)N(H)CH₂-ψ

I-72 methyl CN H —C(O)N(H)CH₂-ψ

I-73 methyl H F —C(O)N(H)CH₂-ψ

I-74 methyl H F —C(O)N(H)CH₂-ψ

Where in Table 1, ψ is a bond to A¹.

TABLE 2 Compound No. Compound Structure II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme 1 depicts an exemplaryprocedure for preparing substituted imidazo[1,5-a]pyrimidine compounds.In the first step, 5-amino-1H-imidazole-4-carboxamide (R^(i)═H) A iscondensed with pentane-2,4-dione (R^(ii)═R^(iv)═Me; R^(iii)═H) in aceticacid at 80° C. to afford2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide B.

Treatment of carboxamide B with phosphoryl chloride affords theintermediate nitrile which is hydrolyzed under acidic conditions andisolated as ethyl ester C. Hydrolysis of ethyl ester C under basicconditions provides 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylicacid D.

The synthetic route illustrated in Scheme 2 depicts an exemplaryprocedure for preparing substituted imidazo[1,5-a]pyrimidine compounds.In the first step, coupling of carboxylic acid D with a variety ofsubstituted aromatic or heteraromatic amines may be accomplished usingstandard peptide coupling procedures, such as HATU and/or HOBT in DMF inthe presence of DIPEA. Alternatively, carboxylic ester C may be treatedwith AlMe₃ to afford the intermediate Weinreb amide, which afterreaction with an amine provides substituted amide E. In some cases, thereaction is performed in a stepwise manner where a bromo oriodo-substituted aromatic or heteraromatic amine is coupled with theWeinreb amide to form the iodo or bromo-substituted amide F. The bromoor iodo moiety may be used to couple a variety of functional groupsusing standard coupling procedures, such as acetylenes using Sonogashiracoupling, boronic acids using Suzuki coupling, and amines using Buchwaldcoupling to produce substituted amide E.

The reaction procedures in Scheme 2 are contemplated to be amenable topreparing a wide variety of substituted imidazo[1,5-a]pyrimidinecarboxamide compounds having different substituents at the A¹ and Y¹positions. Furthermore, if a functional group that is part of the A¹and/or Y¹ would not be amenable to a reaction condition described inScheme 2, it is contemplated that the functional group can first beprotected using standard protecting group chemistry and strategies, andthen the protecting group is removed after completing the desiredsynthetic transformation. See, for example, Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991, for further description of protecting chemistry and strategies. Incertain other embodiments, a functional group in substituent A¹ and Y¹can converted to another functional group using standard functionalgroup manipulation procedures known in the art. See, for example,“Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds.,1991-1992).

III. THERAPEUTIC APPLICATIONS

The invention provides methods of treating medical disorders, such asGaucher disease, Parkinson's disease, Lewy body disease, dementia,multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, ananxiety disorder, major depression, polycystic kidney disease, type 2diabetes, open angle glaucoma, multiple sclerosis, and multiple myeloma,using the substituted imidazo[1,5-a]pyrimidine, related compounds, andpharmaceutical compositions described herein. Treatment methods includethe use of substituted imidazo[1,5-a]pyrimidine or related organiccompounds described herein as stand-alone therapeutic agents and/or aspart of a combination therapy with another therapeutic agent. Althoughnot wishing to be bound by a particular theory, it is understood thatsubstituted imidazo[1,5-a]pyrimidines and related organic compoundsdescribed herein may activate glucocerebrosidase (Gcase).

Methods of Treating Medical Disorders

One aspect of the invention provides a method of treating disorderselected from the group consisting of Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, and multiple myeloma. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a substituted imidazo[1,5-a]pyrimidine or related organiccompound described herein to treat the disorder. The compound may be acompound of Formula I, which, as described above in Section II, isrepresented by:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   R¹ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,        —(C₁₋₄alkylene)-(C₁₋₄alkoxyl), cyclopropyl, cyano, chloro, or        fluoro;    -   R² is hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,        cyclopropyl, cyano, chloro, or fluoro;    -   R³ represents independently for each occurrence hydrogen or        C₁₋₄alkyl;    -   R⁴ represents independently for each occurrence hydrogen,        C₁₋₄alkyl, or —C(O)R³;    -   X¹ is one of the following:        -   (a) a carbonyl-containing linker selected from —C(O)N(H)-ψ,            —C(O)N(H)(C₁₋₆alkylene)-ψ, and —C(O)-(3-6 membered            heterocycloalkylene containing at least one ring —N(H)—            group)-ψ; where ψ is a bond to A¹; or        -   (b) an amine-containing linker selected from            —(C₁₋₄alkylene)-N(H)-ψ and            —(C₁₋₄alkylene)-N(H)-(C₁₋₄alkylene)-ψ;    -   A¹ is a cyclic group selected from:        -   C₃₋₁₀ cycloalkyl, phenyl, or 5-6 membered heteroaryl, each            of which is substituted by 1 or 2 occurrences of Y¹ and 0,            1, 2, or 3 occurrences of Y²; and        -   a bicyclic carbocyclyl that is partially unsaturated or a            mono-cyclic or bicyclic heterocyclyl, each of which is            substituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or            3 occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl or a 3-10 membered heterocyclyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl,            C₃₋₇-cycloalkyl, —O—C₃₋₇cycloalkyl, —O-(3-6 membered            heterocyclyl), —O-(6-10 membered aryl), or —O—(C₂₋₆alkynyl);        -   C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,            —C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆alkenyl; or        -   halogen or cyano;    -   Y² represents, independently for each occurrence, deuterium,        C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl,        C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, azido, —N(R³)₂,        —(C₁₋₆alkylene)-(5-6 membered heterocyclyl),        —(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl-substituted        C₃₋₆cycloalkyl; and    -   n is 1, 2, or 3.

In certain embodiments, the disorder is Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy. Incertain embodiments, the disorder is Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy. Incertain other embodiments, the disorder is Gaucher disease. In certainembodiments, the disorder is Parkinson's disease. In certainembodiments, the disorder is Lewy body disease. In certain embodiments,the disorder is dementia. In certain embodiments, the disorder is adementia selected from the group consisting of Alzheimer's disease,frontotemporal dementia, and a Lewy body variant of Alzheimer's disease.In certain embodiments, the disorder is multiple system atrophy.

In certain embodiments, the disorder is an anxiety disorder, such aspanic disorder, social anxiety disorder, or generalized anxietydisorder.

Efficacy of the compounds in treating Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, and multiple myeloma may be evaluated by testing thecompounds in assays known in the art for evaluating efficacy againstthese diseases and/or, e.g., for activation of glucocerebrosidase(Gcase), as discussed in the Examples below.

In certain embodiments, the patient is a human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Section II, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A. In certain otherembodiments, the compound is a compound of Formula I-B or I-C or acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-B or I-C.

The description above describes multiple embodiments relating to methodsof treating various disorders using certain substitutedimidazo[1,5-a]pyrimidines or related organic compounds. The patentapplication specifically contemplates all combinations of theembodiments. For example, the invention contemplates methods fortreating Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy by administering a therapeuticallyeffective amount of a compound of Formula I-A wherein A¹ is phenyl or5-6 membered heteroaryl, each of which is substituted once by Y¹ and 0,1, or 2 occurrences of Y², and Y¹ is 2-8 membered heteroalkyl.

Medical Use and Preparation of Medicament

Another aspect of the invention relates to compounds and compositionsdescribed herein for use in treating a disorder described herein.Another aspect of the invention pertains to use of a compound orcomposition described herein in the preparation of a medicament fortreating a disorder described herein.

Combination Therapy

The invention embraces combination therapy, which includes theadministration of a substituted imidazo[1,5-a]pyrimidine or relatedcompound described herein (such as compound of Formula I, I-A, I-B, orI-C) and a second agent as part of a specific treatment regimen intendedto provide the beneficial effect from the co-action of these therapeuticagents. The beneficial effect of the combination may includepharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents.

Exemplary second agents for use in treating Gaucher disease include, forexample, taliglucerase alfa, velaglucerase alfa, eliglustat, andmiglustat. Exemplary second agents for use in treating Parkinson'sdisease include, for example, levodopa, pramipexole, ropinirole,rotigotine, and apomorphine.

IV. PHARMACEUTICAL COMPOSITIONS

The invention provides pharmaceutical compositions comprising asubstituted imidazo[1,5-a]pyrimidine or related organic compounddescribed herein, such as a compound of Formula I, I-A, I-B, or I-C. Incertain embodiments, the pharmaceutical compositions preferably comprisea therapeutically-effective amount of one or more of the substitutedimidazo[1,5-a]pyrimidine or related organic compounds described above,formulated together with one or more pharmaceutically acceptablecarriers. As described in detail below, the pharmaceutical compositionsof the present invention may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets (e.g., those targeted for buccal,sublingual, and/or systemic absorption), boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration by,for example, subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration.

The amount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will generally be that amountof the compound which produces a therapeutic effect. Generally, out ofone hundred per cent, this amount will range from about 0.1 per cent toabout ninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

V. KITS FOR USE IN MEDICAL APPLICATIONS

Another aspect of the invention provides a kit for treating a disorder.The kit comprises: i) instructions for treating a medical disorder, suchas Gaucher disease, Parkinson's disease, Lewy body disease, dementia, ormultiple system atrophy; and ii) a substituted imidazo[1,5-a]pyrimidineor related organic compound described herein, such as a compound ofFormula I, I-A, I-B, or I-C. The kit may comprise one or more unitdosage forms containing an amount of a substitutedimidazo[1,5-a]pyrimidine or related organic compound described herein,such as a compound of Formula I, that is effective for treating saidmedical disorder, e.g., Gaucher disease, Parkinson's disease, Lewy bodydisease, dementia, or multiple system atrophy.

The description above describes multiple aspects and embodiments of theinvention, including substituted imidazo[1,5-a]pyrimidines and relatedorganic compounds, compositions comprising a substitutedimidazo[1,5-a]pyrimidine or related organic compounds, methods of usingthe substituted imidazo[1,5-a]pyrimidine or related organic compounds,and kits. The patent application specifically contemplates allcombinations and permutations of the aspects and embodiments. Forexample, the invention contemplates treating Gaucher disease,Parkinson's disease, Lewy body disease, dementia, or multiple systematrophy in a human patient by administering a therapeutically effectiveamount of a compound of Formula I-A. Further, for example, the inventioncontemplates a kit for treating Gaucher disease, Parkinson's disease,Lewy body disease, dementia, or multiple system atrophy, the kitcomprising instructions for treating Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy and ii)a substituted imidazo[1,5-a]pyrimidine or related organic compounddescribed herein, such as a compound of Formula I-A.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1 PREPARATION OF 2,4-DIMETHYLIMIDAZO81,5-alPYRIMIDINE-8-CARBOXAMIDE (1)

A solution of pentane-2,4-dione (1.5 g, 11.8 mmol) in MeOH (10 mL) wascharged with acetic acid (10 mL) and 4-amino-1H-imidazole-5-carboxamide(1.8 g, 17.8 mmol) at room temperature. The resulting solution washeated to 80° C. for 5 h. The reaction mixture was concentrated in vacuoto dryness to obtain crude residue which was triturated with diethylether to afford compound 1 as a yellow solid (2 g, 88%). ¹H NMR (400MHz, DMSO-d₆) δ8.37 (s, 2H), 7.21(s, 1H), 6.81 (s, 1H), 2.63 (s, 3H),2.50 (s, 3H). ES-MS m/z 191.00 (M+H)⁺.

Example 2 PREPARATION OF ETHYL2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXYLATE (2)

A solution of 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide 1 (7 g,36.8 mmol) in POCl₃ (140 mL) was heated to reflux at 80° C. for 3 h. Thereaction mixture was concentrated in vacuo to obtain a crude residuewhich was diluted with water (50 mL), basified with saturated NaHCO₃solution and extracted with dichloromethane (DCM) (3×50 mL). Thecombined organic layer was dried over sodium sulfate and the solventremoved under vacuum to give a yellow solid which was dissolved inethanol (100 mL) and added to conc. H₂SO₄ (10 mL) and heated to 80° C.for 16 h. Then, the solvent was removed under vacuum to remove ethanol,diluted with water (100 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was dried over sodium sulfate and the solventremoved under vacuum to obtain crude compound. The crude compound waspurified by FCC (eluent, 3-5% methanol in DCM) to afford compound 2 as ayellow solid (7 g, 52%). ¹H NMR (400 MHz, CDCl₃) δ7.97 (s, 1H), 6.56 (s,1H), 4.50 (q, J=6.80 Hz, 2H), 2.67 (s, 3H), 2.66 (s, 3H), 1.47 (t,J=7.60 Hz, 3H).

Example 3 PREPARATION OF2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXYLIC ACID (3)

A solution of ethyl 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylate 2(150 mg, 0.68 mmol) in THF:H₂O (10:2 mL) was charged with LiOH (33 mg,1.36 mmol) at room temperature. The reaction mixture was heated toreflux at 50° C. for 16 h. Then, the reaction mixture was diluted withwater (10 mL) and extracted with ethyl acetate (2×10 mL). The separatedaqueous layer was acidified (pH=5) with acetic acid and extracted with10% methanol in DCM (3×10 mL). The combined organic layer was dried oversodium sulfate and the solvent removed under vacuum to afford compound 3as an off-white solid (60 mg, 45%). ¹H NMR (400 MHz, DMSO): δ8.22 (s,1H), 6.70 (s, 1H), 2.61 (s, 3H), 2.48 (s, 3H). ES-MS m/z 192.00 [M+H]⁻.

Example 4 PREPARATION OF N-(4-IODOPHENYL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE (4)

A solution of 4-iodoaniline (299 mg, 1.14 mmol) in toluene (4 mL) at 0°C. was charged with a 2M solution of trimethyl aluminum in toluene (2.2mL, 5.6 mmol) and stirred at 0° C. for 30 min. To the resulting solutionwas added a solution of ethyl2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylate 2 (250 mg, 1.14 mmol)in toluene (1 mL) and stirred for 10 min. The reaction mixture washeated to 120° C. for 16 h. Then, the reaction mixture was quenched with1N HCl and extracted with ethyl acetate (2×10 mL) to obtain crudecompound. The crude compound was purified by FCC (eluent, 2-4% methanolin DCM) to afford product 4 as an off-white solid (260 mg, 58%). ¹H NMR(400 MHz, CDCl₃) δ9.84 (br s, 1H), 8.00 (s, 1H), 7.63-7.67 (m, 2H),7.57-7.61 (m, 2H), 6.56 (s, 1H), 2.68 (s, 3H), 2.66 (s, 3H). ES-MS m/z393.00 (M+H)⁺.

Example 5 PREPARATION OF N-(4-ETHYNYLPHENYL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A solution of 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3(57 mg, 0.29 mmol) in DMF (0.5 mL) was charged with HATU (165 mg, 0.43mmol), DIPEA (0.15 mL, 0.87 mmol) and 4-ethynylaniline (42 mg, 0.35mmol) at room temperature and stirred for 48 h. Then, the reactionmixture was quenched with water (1 mL), the solid precipitated out wasfiltered and dried to obtain crude compound. The crude compound waspurified by washing with methanol to afford the title compound as anoff-white solid (40 mg, 46%). ¹H NMR (400 MHz, DMSO-d₆) δ10.34 (s, 1H),8.47 (s, 1H), 7.84 (d, J=8.53 Hz, 2H), 7.46 (d, J=8.53 Hz, 2H), 6.90 (s,1H), 4.08 (s, 1H), 2.70 (s, 3H), 2.60 (s, 3H). ES-MS m/z 291.10 (M+H)⁺.HPLC purity 99.6%.

Example 6 PREPARATION OFN-(4-(3-METHOXYPROP-1-YN-1-YL)PHENYL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A solution ofN-(4-iodophenyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide 4(100 mg, 0.25 mmol) in DMF (1 mL) was purged with argon for 15 min. Tothe resulting solution was added 3-methoxyprop-1-yne (47 mg, 0.68 mmol),copper iodide (1 mg, 0.05 mmol), triphenyl phosphine (13 mg, 0.05 mmol),triethylamine (0.1 mL, 0.075 mmol) and catalyst PdCl₂(PPh₃)₂ (3.5 mg,0.05 mmol) and purged with argon for another 30 min. The reactionmixture was stirred at room temperature for 16 h. The reaction mixturewas diluted with water (5 mL) and extracted with ethyl acetate (3×10 mL)to obtain crude compound. The crude compound was purified bysupercritical fluid chromatograph (SFC) (Column: Silica 2-ethylpyridine; Dimensions: 30×250mm, 5μsize; Method: Mobile phase A—CO₂,Mobile phase B—5mM Ammonium formate in MeOH; Gradient Programme: 10%co-solvent to 50% maximum) to afford the title compound as a yellowsolid (40 mg, 47%). ¹H NMR (400 MHz, CDCl₃) δ9.94 (s, 1H), 8.00 (s, 1H),7.76 (d, J=8.57 Hz, 2H), 7.45 (d, J=9.00 Hz, 2H), 6.55 (d, J=0.86 Hz,1H), 4.33 (s, 2H), 3.46 (s, 3H), 2.68 (s, 3H), 2.66 (s, 3H). ES-MS m/z335.20(M+H)⁺. HPLC purity 97.7%.

Example 7 PREPARATION OF 2,4-DIMETHYL-N-(4-(OXAZOL-4-YL)PHENYL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a solution of 4-(4-nitrophenyl)oxazole (500 mg, 2.60 mmol) inMeOH:THF (3:3 mL) was added 10% Pd/C (50 mg, 10% wt) under nitrogenatmosphere at room temperature. The reaction mixture was stirred underhydrogen atmosphere at room temperature for 16h. Then, the reactionmixture was filtered over a pad of celite and the filtrate wasconcentrated under vacuum to afford crude compound. The crude compoundwas purified by FCC (eluent, 30% ethyl acetate in hexane) to afford4-(oxazol-4-yl)aniline as a light brown viscous oil (260 mg, 62%). ¹HNMR (400 MHz, DMSO-d₆) δ8.27-8.34 (m, 2H), 7.40-7.46 (m, 2H), 6.56-6.62(m, 2H), 5.23 (s, 2H). ES-MS m/z 160.95 (M+H)⁺.

A solution of 4-(oxazol-4-yl)aniline (90 mg, 0.54 mmol) in toluene (15mL) at 0° C. was charged with 2M solution of trimethyl aluminum intoluene (0.9 mL, 0.54 mmol) and stirred at 0° C. for 30 min. To theresulting solution was added a solution ofethyl-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylate 2 (100 mg, 0.45mmol) in toluene (5 mL) and stirred for 10 min. The reaction mixture washeated to 100° C. for 16 h. The reaction mixture was quenched with 1NHCl and extracted with ethyl acetate (2×10 mL) to obtain crude compound.The crude compound was purified by FCC (eluent, 2-4% methanol in DCM) toafford the title compound as an off-white solid (30 mg, 19%). ¹H NMR(400 MHz, CDCl₃) δ9.93 (br s, 1H), 8.01 (s, 1H), 7.93 (d, J=1.76 Hz,2H), 7.88 (d, J=8.38 Hz, 2H), 7.75 (d, J=8.38 Hz, 2H), 6.56 (s, 1H),2.68 (s, 6H). ES-MS m/z 334.25(M+H)⁺. HPLC purity 97.7%.

Example 8 PREPARATION OF2,4-DIMETHYL-N-(4-(OXAZOL-2-YL)PHENYL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A solution of 4-(oxazol-2-yl)aniline (80 mg, 0.54 mmol) in toluene (4mL) at 0° C. was charged with 2M solution of trimethyl aluminum intoluene (0.9 mL, 1.60 mmol) and stirred at 0° C. for 30 min. To theresulting mixture was added a solution of ethyl2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylate 2 (100 mg, 0.45 mmol)in toluene (1 mL) and stirred for 10 min. Then, the reaction mixture washeated to 100° C. for 14 h. Next, the reaction mixture was quenched with1N HCl and extracted with DCM (2×10 mL) to obtain crude compound. Thecrude compound was purified by FCC (eluent, 1% methanol in DCM) toafford the title compound as a yellow solid (25 mg, 16%). ¹H NMR (400MHz, DMSO-d₆) δ10.04 (s, 1H), 8.04 (d, J=8.9 Hz, 2H), 8.00 (d, J=8.8 Hz,1H), 7.90 (d, J=8.9 Hz, 2H), 7.69 (s, 1H), 7.22 (d, J=8.8 Hz, 1H), 6.56(s, 1H), 2.68 (s, 6H). ES-MS m/z 333.35 (M+H)⁺. HPLC purity 92.5%.

Example 9 PREPARATION OFN-(6-ETHYNYLPYRIDIN-3-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a solution of 6-bromopyridin-3-amine (500 mg, 2.89 mmol) in CH₃CN:DMF(3:2 mL) was added CuI (219 mg, 1.15 mmol) and triethylamine (2 mL, 14.4mmol) and the solution was purged with argon for 15 min.Ethynyltrimethylsilane (1.2 mL, 8.67 mmol) and tetrakis(triphenylphosphine)Pd(O) (100 mg, 0.086 mmol) were added and the solution waspurged for another 30 min. The reaction mixture was heated to 45° C. for2.5 h. Then, the reaction mixture was diluted with ethyl acetate (100mL) and washed with saturated NaHCO₃ solution (50 mL). The aqueous layerwas re-extracted with ethyl acetate (3×50 mL). The combined organiclayer was washed with water (2×50 mL), followed by brine and dried oversodium sulphate and concentrated in vacuo to afford6-((trimethylsilyl)ethynyl)pyridin-3-amine 5 (776mg, 70%). ¹H NMR (400MHz, CDCl₃) δ8.04 (s, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.91(d, J=7.8 Hz,1H), 3.85 (br s, 2H), 0.24 (s, 9H). ES-MS m/z 191.00 (M+H)⁺.

To a solution of 6-((trimethylsilyl)ethynyl)pyridin-3-amine 5 (104 mg,0.50 mmol) in toluene (4 mL) at 0° C. was charged a 2M solution oftrimethyl aluminum in toluene (0.9 mL, 1.80 mmol) and the mixturestirred at 0° C. for 30 min. A solution of ethyl2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylate 2 (100 mg, 0.45 mmol)in toluene (1 mL) was then added and the mixture was stirred for 10 minfollowed by a further 14 h at 100° C. Then, the reaction mixture wasquenched with 1N HCl and extracted with DCM (2×10 mL) to obtain crudeproduct. The crude product was purified by FCC (eluent, 1% methanol inDCM) to afford2,4-dimethyl-N-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)imidazo[1,5-a]pyrimidine-8-carboxamideas a yellow solid (70 mg, 42%), which was directly used in the nextstep.

To a solution of2,4-dimethyl-N-(6-((trimethylsilyl)ethynyl)pyridin-3-yl)imidazo[1,5-a]pyrimidine-8-carboxamide(60 mg, 0.165 mmol) in MeOH (10 mL) was charged K₂CO₃ (68 mg, 0.49 mmol)and the mixture stirred at room temperature for 3 h. Then, the reactionmixture was concentrated in vacuo to obtain a crude product which waspurified by FCC (eluent, 20-25% ethyl acetate in hexane) to afford thetitle compound as an off-white solid (12 mg, 25%). ¹H NMR (400 MHz,CDCl₃) δ10.04 (br s, 1H), 8.66 (d, J=2.2 Hz, 1H), 8.57 (dd, J=2.4, 8.7Hz, 1H), 8.04 (s, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.60 (s, 1H), 3.12 (s,1H), 2.71 (s, 3H), 2.69 (s, 3H). ES-MS m/z 291.95 (M+H)⁺. HPLC purity96.2%.

Example 10 PREPARATION OF2,4-DIMETHYL-N-(5-METHYL-1H-IMIDAZOL-2-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A solution of 5-methyl-1H-imidazol-2-amine (48 mg, 0.50 mmol) in toluene(4 mL) at 0° C. was charged with 2M solution of trimethyl aluminum intoluene (0.9 mL, 1.80 mmol) and stirred at 0° C. for 30 min. To theresulting mixture was added a solution of ethyl2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylate 2 (100 mg, 0.45 mmol)in toluene (1 mL) and the mixture stirred for 10 min. Then, the reactionmixture was heated to 100° C. for 14 h. Next. the reaction mixture wasquenched with 1N HCl and extracted with DCM (2×10 mL) to obtain crudecompound. The crude compound was purified by FCC (eluent, 1% methanol inDCM) to afford the title compound as white solid (29 mg, 23%). ¹H NMR(400 MHz, CDCl₃) δ8.04 (s, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 2.69 (s,6H), 2.26 (s, 3H). ES-MS m/z 271.30 (M+H)⁺. HPLC purity 99.9%.

Example 11 PREPARATION OF2,4-DIMETHYL-N-(2-METHYL-1H-INDOL-5-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 2-methyl-1H-indol-5-amine (46 mg, 0.314 mmol) and HATU (149 mg,0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.582 mmol), and thereaction mixture was stirred at room temperature for 16 hours until thereaction was complete. Then, the suspension was diluted with H₂O (3 mL),and the precipitated solid was collected by filtration, washed withminimum DCM and Et₂O, and dried in vacuo to give the title compound (39mg, 39%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.82 (s, 1H),10.04 (s, 1H), 8.44 (s, 1H), 7.89 (s, 1H), 7.29-7.21 (m, 2H), 6.87 (s,1H), 6.10 (s, 1H), 2.89 (s, 3H), 2.70 (s, 3H), 2.37 (s, 3H). ES-MS m/z:320.0 (M+H⁺). LC-MS Purity (214 nm) : >99%; t_(R)=1.60 min.

Example 12 PREPARATION OFN-(1H-INDAZL-5-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A mixture of 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3(50 mg, 0.26 mmol), 1H-indazol-5-amine (42 mg, 0.314 mmol) and HATU (57mg, 0.39 mmol.) in DMF/NMM (1 mL/0.1 mL) was stirred at room temperaturefor 12 hours. Then, the reaction mixture was diluted with water (2 mL),stirred at room temperature for 0.5 hour and then filtered. The solidwas washed with water (1 mL), DCM (2 mL), Et₂O (2 mL) and dried in vacuoto give the title compound (28 mg, 35.0%) as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ12.99 (s, 1H), 10.23 (s, 1H), 8.46 (s, 1H), 8.31 (s, 1H),8.05 (s, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 6.89 (s,1H), 2.71 (s, 3H), 2.62 (s, 3H). ES-MS m/z: 307.2 [M+H]⁺. LC-MS Purity(254 nm): >98%; t_(R)=1.42 min.

Example 13 PREPARATION OF2,4-DIMETHYL-N-(4-METHYL-2-OXO-2H-CHROMEN-7-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.26mmol), HATU (148 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol) in 1 mLof DMF was added 7-amino-4-methyl-2H-chromen-2-one (55 mg, 0.31 mmol).The reaction mixture was stirred at 70° C. for 16 h until the reactionwas complete. The solid was collected by filtration, washed with H₂O,DCM and diethyl ether to give the title compound (42.5 mg, 46.7%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.56 (s, 1H), 8.50 (s, 1H),8.03 (d, J=2.0 Hz, 1H), 7.80 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.74 (d, J=8.8Hz, 1H), 6.92 (d, J=0.8 Hz, 1H), 6.27 (d, J=1.2 Hz, 1H), 2.71 (s, 3H),2.61 (s, 3H), 2.42 (d, J=0.8 Hz, 3H). ES-MS m/z: 349.1 [M+H]⁺. HPLCPurity (214 nm): >94%; t_(R)=8.55 min.

Example 14 PREPARATION OF2,4-DIMETHYL-N-(2-OXO-2,3-DIHYDRO-1H-INDOL-5-YL)IMIDAZO[1,5-a]PYRIMIDINE-3-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (0.050 g, 0.262mmol), 5-amino-2,3-dihydro-1H-indol-2-one (0.046 g, 0.314 mmol) and HATU(0.149 g, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524mmol), and the reaction mixture was stirred at room temperature for 16hours until the reaction was complete. The suspension was diluted withH₂O (3 mL), and the precipitated solid was collected by filtration,washed with minimum DCM and Et₂O, and dried in vacuo to give the titlecompound (0.036 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) δ10.30 (s, 1H),10.08 (s, 1H), 8.44 (s, 1H), 7.72 (s, 1H), 7.54 (d, J=8.4 Hz, 2.0 Hz,1H), 6.88 (s, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.50 (s, 2H), 2.70 (s, 3H),2.59 (s, 3H). ES-MS m/z: 322.0 (M+H⁺). LC-MS Purity (254 nm): 98%;t_(R)=1.36 min.

Example 15 PREPARATION OFN-(1H-INDAZOL-6-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.26mmol), HATU (148 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol) in 1 mLof DMF was added 1H-indazol-6-amine (42 mg, 0.31 mmol). The reaction wasstirred at room temperature for 16 hours until the reaction wascomplete. The solid was collected by filtration, washed with H₂O, DCMand diethyl ether to give the title compound (36.7 mg, 46%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ12.92 (s, 1H), 10.39 (s, 1H), 8.48 (s,1H), 8.38 (s, 1H), 7.98 (s, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.23 (dd, J=1.2Hz, 7.2 Hz, 1H), 6.91 (s, 1H), 2.71 (s, 3H), 2.62 (s, 3H). ES-MS m/z:307.1 [M+H]⁺. LC-MS Purity (214 nm): >99%; t_(R)=1.47 min.

Example 16 PREPARATION OFN-(2H-1,3-BENZODIOXOL-5-YL)-2,4-DIMETHYLIMIDAZO [1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.26mmol), HATU (148 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol) in 1 mLDMF was added 2H-1,3-benzodioxol-5-amine (43 mg, 0.31 mmol). Thereaction was stirred at room temperature for 16 hours until the reactionwas complete. The solid was collected by filtration, washed with H₂O,DCM and diethyl ether to give the title compound (28.7 mg, 35.8%) as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.09 (s, 1H), 8.44 (s, 1H),7.55 (d, J=2.4 Hz, 1H), 7.18 (dd, J=1.6 Hz, 8.0 Hz, 1H), 6.90-6.87 (m,2H), 6.00 (s, 2H), 2.69 (s, 3H), 2.58 (s, 3H). ES-MS m/z: 311.1 [M+H]⁺.HPLC Purity (214 nm): >97%; t_(R)=8.53 min.

Example 17 PREPARATION OFN-(2-HYDROXY-4-METHYLQUINOLIN-6-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A mixture of 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3(50 mg, 0.26 mmol), 6-amino-4-methylquinolin-2-ol (54.6 mg, 0.314 mmol)and HATU (148 mg, 0.39 mmol.) in DMF/NMM (1 mL/0.1 mL) was stirred atroom temperature for 12 hours. Then, the reaction mixture was dilutedwith water (2 mL), stirred at room temperature for 0.5 hour and thenfiltered. The solid was washed with water (1 mL), DCM (2 mL), Et₂O (2mL) and dried to give the title compound (60 mg, 67%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ11.56 (s, 1H), 10.23 (s, 1H), 8.47 (s, 1H),8.30 (d, J=2.4 Hz, 1H),), 7.88 (dd, J=2.0 Hz, 8.8 Hz, 1H), 7.29 (d,J=9.2 Hz, 1H), 6.89 (d, J=1.2 Hz, 1H), 6.42 (s, 1H), 2.71 (s, 3H), 2.60(s, 3H), 2.43 (s, 3H). ES-MS m/z: 348.1 [M+H]⁺. HPLC Purity (214 nm):97.11%; t_(R)=7.49 min.

Example 18 PREPARATION OFN-[3-METHOXY-4-(1,3-OXAZOL-5-YL)PHENYL]-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 3-methoxy-4-(1,3-oxazol-5-yl)aniline (60 mg, 0.314 mmol) and HATU(149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol),and the reaction mixture was stirred at room temperature for 16 hoursuntil the reaction was complete. The suspension was diluted with H₂O (3mL), and the precipitated solid was collected by filtration, washed withminimum DCM and Et₂O, and dried in vacuo to give the title compound (45mg, 47%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.34 (s,1H), 8.49 (s, 1H), 8.39 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.66 (d, J=8.4Hz, 1H), 7.51 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.46 (s, 1H), 6.91 (d, J=1.2Hz, Hz, 1H), 3.97 (s, 3H), 2.71 (s, 3H), 2.61 (s, 3H). ES-MS m/z: 364.0[M+H]⁺. HPLC Purity (214 nm): 98%; t_(R)=8.65 min.

Example 19 PREPARATION OF2,4-DIMETHYL-N-(1,2,3,4-TETRAHYDROISOQUINOLINE-6-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a mixture of 6-nitro-1,2,3,4-tetrahydroquinoline (200 mg, 0.772 mmol)and TEA (156 mg, 1.544 mmol) in 6 mL of dioxane and 1 mL of H₂O wasadded Boc₂O (168 mg, 0.772 mmol), and the reaction mixture was stirredat room temperature for 2 h and concentrated in vacuo. Saturated sodiumbicarbonate was added to the residue, and the mixture was extracted withDCM. The organic layer was washed with brine, dried over anhydrousMg₂SO₄ and concentrated to give crude tert-butyl6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 100%) whichwas used directly in the next step. ES-MS m/z: 223 (M-55)⁺. LC-MS Purity(254 nm): >98%; t_(R)=2.00 min.

To the suspension of tert-butyl6-nitro-1,2,3,4-tetrahydroquinoline-2-carboxylate (220 mg, 0.772 mmol)and NH₄Cl (330 mg, 6.176 mmol) in 6 mL of EtOH and 4 mL of H₂O was addedFe powder (173 mg, 3.088 mmol) in portions. The reaction mixture wasstirred at 70° C. for 2 h, cooled down to room temperature and thenfiltered through Celite. The filter cake was washed with ethanol. Theorange solution was concentrated, and the residue was purified byprep-HPLC (MeCN/10 mM NH₄HCO₃) to give tert-butyl6-amino-1,2,3,4-tetrahydroquinoline-2-carboxylate as oil (150 mg, 78% 2steps). ¹H NMR (400 MHz, CDCl₃) δ6.89 (d, J=8.0 Hz, 1H), 6.54 (dd, J=8.0Hz, 2.0 Hz, 1H), 6.47 (s, 1H), 6.45 (s, 2H), 3.60-3.58 (m, 4H), 2.73 (t,J=5.6 Hz, 2H), 1.48 (s, 9H).

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), tert-butyl 6-amino-1,2,3,4-tetrahydroquinoline-2-carboxylate (72mg, 0.288 mmol) and HATU (120 mg, 0.314 mmol) in DMF (1.0 mL) was addedDIPEA (0.1 mL, 0.524 mmol), and the reaction mixture was stirred at roomtemperature for 16 h until the reaction was complete. The crude productwas purified by prep-HPLC (MeCN/10 mM NH₄HCO₃) to give the Boc-protectedform of the title compound as a white solid (62 mg, 56%). ES-MS m/z: 422(M+H⁺). LC-MS Purity (254 nm): 96%; t_(R)=1.93 min.

TFA (0.5 mL) was added to Boc-protected product from the procedure above(62 mg, 0.152 mmol) at 0° C. The mixture was stirred at room temperaturefor 2 h, diluted with DCM, and basified to pH ˜8 with saturated NaHCO₃.The resulting mixture was separated, and the aqueous phase was extractedwith DCM. The combined organic phases were dried over anhydrous Na₂SO₄,and concentrated in vacuo. The residue was purified by prep-HPLC(MeCN/10 mM NH₄HCO₃) to give the title compound as a white solid (30 mg,64%). ¹H NMR (400 MHz, DMSO-d₆) δ10.07 (s, 1H), 8.45 (s, 1H), 7.53 (s,1H), 7.48 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.88 (d, J=0.8 Hz,1H), 3.81 (s, 2H), 2.94 (t, J=5.6 Hz, 2H), 2.70-2.69 (m, 5H), 2.60 (s,3H),. ES-MS m/z: 322.2 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=6.68min.

Example 20 PREPARATION OF2,4-DIMETHYL-N-(2-METHYL-4-OXO-4H-CHROMEN-7-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.26mmol), HATU (148 mg, 0.39 mmol), and DIPEA (0.09 mL, 0.52 mmol) in 1 mLof DMF was added 7-amino-2-methyl-4H-chromen-4-one (55 mg, 0.31 mmol).The reaction mixture was stirred at 70° C. for 16 hours until thereaction was complete. The solid was collected by filtration, washedwith H₂O, DCM and diethyl ether to give the title compound (24.2 mg,26.2) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.66 (s, 1H), 8.52(s, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.73 (dd,J=2.0Hz, 8.8 Hz, 1H), 6.94 (s, 1H), 6.19 (s, 1H), 2.72 (s, 3H), 2.62 (s,3H), 2.39 (s, 3H). ES-MS m/z: 349.1 [M+H]⁺. LC-MS Purity (214 nm): >99%;t_(R)=1.50 min; HPLC Purity (214 nm): >98%; t_(R)=8.15 min.

Example 21 PREPARATION OFN-(1,2-BENZOXAZOL-5-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To an ice cold stirred solution of SnCl₄ (1.828 g, 7.02 mmol) in 12M HCl(0.5 mL) was added 5-nitro-1,2-benzoxazole (140 mg, 0.86 mmol) in oneportion at 0° C. Then, 5 minutes later, a solution of SnCl₂. 2H₂O (792mg, 3.51 mmol) in 12M HCl (0.5 mL) was added dropwise at 0° C. to thereaction mixture, followed by the addition of another 1.0 mL of 12M HCl.Then, the reaction mixture was stirred at room temperature for 3 hours,and extracted with Et₂O. The aqueous layer was basified to pH -8 withsaturated NaHCO₃, and extracted with EtOAc. The organic phase was driedover anhydrous Na₂SO₄, filtered, concentrated and dried in vacuo to give1,2-benzoxazol-5-amine as a colorless solid (110 mg, 95%). ¹H NMR (400MHz, CDCl₃) δ8.54 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.94 (dd, J=8.4 Hz,2.0 Hz, 1H), 6.91 (d, J=2.0 Hz, 1H) ES-MS m/z: 135.1 [M+H]⁺. LC-MSPurity (214 nm): 90%; t_(R)=1.32 min.

To a solution of 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid3 (100 mg, 0.524 mmol) and HATU (259 mg, 0.681 mmol) in DMF (1 mL) wasadded DIPEA (136 mg, 1.048 mmol), and the reaction mixture was stirredat room temperature for 2 hours until the reaction was complete. Thesuspension was diluted with H₂O (3 mL), and the precipitated solid wascollected by filtration, washed with minimum DCM and Et₂O, and dried invacuo to give the intermediate ester (105 mg, 65%) as a white solid.ES-MS m/z: 310.0 [M+H⁺]. LC-MS Purity (254 nm): 88%; t_(R)=1.61 min.

To a suspension of intermediate ester (105 mg, 0.340 mmol) in DMF (0.5mL) was added a solution of 1,2-benoxazol-5-amine (46 mg, 0.340 mmol) inDMF (0.5 mL). The reaction mixture was stirred at room temperature for 2hours until the reaction was complete, and quenched with the addition ofTFA (5 drops). The precipitated solid was collected by filtration,suspended in DCM, basified with saturated NaHCO₃ to pH ˜8. The aqueouslayer was extracted with DCM, dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by trituration in DCM/Et₂O,collected by filtration, and dried in vacuo to give the title compound(50 mg, 48%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ10.05 (s, 1H),8.72 (s, 1H), 8.55 (s, 1H), 8.07 (s, 1H), 7.68 (dd, J=6.8 Hz, 1.6 Hz,1H), 7.59 (d, J=6.8 Hz, 1H), 6.59 (s, 1H), 2.71 (s, 3H), 2.70 (s, 3H).LC-MS m/z: 308.1 [M+H⁺]. HPLC Purity (214 nm): 98%; t_(R)=8.38 min.

Example 22 PREPARATION OFN-[2-(FURAN-2-YL)-1H-1,3-BENZODIAZOL-5-YL]-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-3-CARBOXAMIDE

A mixture of 4-nitrobenzene-1,2-diamine (1.53 g, 10 mmol),furan-2-carbaldehyde (1.22 g, 13.0 mmol), p-benzoquinone (1.19 g, 11mmol) and 2-propanol (15 mL) in a sealed tube was refluxed for 2 hours.The reaction was diluted with water, filtrated and dried in vacuo togive 2-(furan-2-yl)-5-nitro-1H-1,3-benzodiazole as a yellow solid (1.2g, 52%). LC-MS m/z: 234 (M+1). LC-MS Purity (214 nm): >90%.

A suspension of 2-(furan-2-yl)-5-nitro-1H-1,3-benzodiazole (1.2 g, 5.15mmol) and 10% Pd/C (120 mg) in EtOH (10 mL) was stirred at roomtemperature under H₂ for 2 hours. The mixture was filtered, and thefiltrate was concentrated in vacuo. The residue was purified by silicagel column (MeOH/DCM =1/10) to give2-(furan-2-yl)-1H-1,3-benzodiazol-5-amine as a yellow solid (870 mg,83%). ¹H NMR (400 MHz, DMSO-d₆) δ12.31 (s, 1H), 7.85 (d, J=1.2 Hz, 1H),7.24 (d, J=8.4 Hz, 1H), 7.01 (d, J=3.2 Hz, 1H), 6.67 (m, 2H), 6.53 (q,J=2.0 Hz, 1H), 4.93 (s, 2H). LC-MS m/z: 204 (M+1). LC-MS Purity (214nm):>95%.

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 2-(furan-2-yl)-1H-1,3-benzodiazol-5-amine (57 mg, 0.314 mmol) andHATU (149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.14 mL, 0.786mmol), and the reaction mixture was stirred at room temperature for 16hours until the reaction was complete. The suspension was diluted withH₂O (3 mL), and the precipitated solid was collected by filtration,washed with minimum DCM and Et₂O, and dried in vacuo to give the titlecompound (33.1 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆) δ12.87 (s, 1H), 10.27(d, J=40.0 Hz, 1H), 8.48 (s, 1H), 8.26 (d, J=60.8 Hz, 1H), 7.94 (s, 1H),7.59-7.55 (m, 1H), 7.40 (dd, J=46.4 Hz, 8.0 Hz, 1H), 7.17 (dd, J=16.4Hz, 3.2 Hz, 1H), 6.91 (s, 1H), 6.74-6.73 (m, 1H), 2.71 (s, 3H), 2.62 (s,3H). ES-MS m/z: 373.2 [M+H]⁺. LC-MS Purity (214 nm): 97%; t_(R)=7.35min.

Example 23 PREPARATION OF2,4-DIMETHYL-N-(2-METHYL-1,3-BENZOTHIAZOL-6-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 2-methyl-1,3-benzothiazol-6-amine (51 mg, 0.314 mmol) and HATU(149 mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol),and the reaction mixture was stirred at room temperature for 16 h untilthe reaction was complete. The suspension was diluted with H₂O (3 mL),and the precipitated solid was collected by filtration, washed withminimum DCM and Et₂O, and dried in vacuo to give the title compound (70mg, 79%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.40 (s, 1H),8.60 (s, 1H), 8.51 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8 Hz,2.0 Hz, 1H), 6.92 (s, 1H), 2.78 (s, 3H), 2.72 (s, 3H), 2.62 (s, 3H).ES-MS m/z: 338.1 [M+H]⁺. HPLC Purity (214 nm): 96%; t_(R)=8.47 min.

Example 24 PREPARATION OFN-(2-3-DIHYDRO-1H-INDEN-5-YL)-2,4-DIMETHYLIMIDAZOLO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 2,3-dihydro-1H-inden-5-amine (42 mg, 0.314 mmol) and HATU (149mg, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol), andthe reaction mixture was stirred at room temperature for 16 h until thereaction was complete. The suspension was diluted with H₂O (3 mL), andthe precipitated solid was collected by filtration, washed with minimumDCM and Et₂O, and dried in vacuo to give the title compound (70 mg, 74%)as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ10.12 (s, 1H), 8.45 (s,1H), 7.70 (s, 1H), 7.49 (dd, J=8.0 Hz, 2.4 Hz, 1H), 7.18 (d, J=8.0 Hz,1H), 6.88 (d, J=1.2 H, 1H), 2.89-2.82 (m, 4H), 2.70 (s, 3H), 2.60 (s,3H), 2.06-1.99 (m, 2H). ES-MS m/z: 307.1 [M+H]⁺. LC-MS Purity (254nm): >99%; t_(R)=1.81 min.

Example 25 PREPARATION OF2,4-DIMETHYL-N-[4-OXO-1,4-DIHYDROQUINOLIN-6-YLPHENYL]IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (70 mg, 0.36mmol), HATU (205 mg, 0.54 mmol), and DIPEA (0.12 mL, 0.72 mmol) in 1 mLof DMF was added 6-amino-1,4-dihydroquinolin-4-one (70 mg, 0.44 mmol).The reaction mixture was stirred at room temperature for 2 days untilthe reaction was complete. The suspension was filtered, and the solidwas washed with H₂O, minimum DCM and Et₂O, and dried in vacuo to givethe title compound (18.5 mg, 15.5%) as a green solid. ¹H NMR (400 MHz,DMSO-d₆) δ11.75 (d, J=5.2 Hz, 1H), 10.35 (s, 1H), 8.53 (d, J=2.4 Hz,1H), 8.48 (s, 1H), 8.03 (dd, J=2.8 Hz, 9.2 Hz, 1H), 7.86 (dd, J=6.0 Hz,7.2 Hz, 1H), 7.55 (d, J=9.2 Hz, 1H), 6.91 (d, J=0.8 Hz, 1H), 6.00 (d,J=6.4 Hz, 1H), 2.71 (s, 3H), 2.62 (s, 3H). ES-MS m/z: 334.0 [M+H]⁺. HPLCPurity (214 nm): >95%; t_(R)=7.02 min.

Example 26 PREPARATION OFN-(4-HYDROXYQUINOLIN-6-YL)2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

The filtrate from Example 25 above was purified by prep-HPLC (MeCN/10 mMNH₄HCO₃) to give the title compound (20.1 mg, 16.7%) as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ10.35 (s, 1H), 8.53 (d, J=2.4 Hz, 1H), 8.48(s, 1H), 8.03 (dd, J=2.8 Hz, 9.2 Hz, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.55(d, J=9.2 Hz, 1H), 6.91 (d, J=0.8 Hz, 1H), 6.00 (d, J=7.6 Hz, 1H), 2.71(s, 3H), 2.62 (s, 3H). ES-MS m/z: 334.1 [M+H]⁺. HPLC Purity (214nm): >95%; t_(R)=7.01 min.

Example 27 PREPARATION OF2,4-DIMETHYL-N-[4-METHYL-3-(1,3-OXAZOL-2-YL)PHENYL]IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A suspension of 3-bromo-4-methylaniline (184 mg, 1.0 mmol),2-(tributylstannyl)-1,3-oxazole (430 mg, 1.2 mmol), CuO (8 mg, 0.1 mmol)and Pd(PPh₃)₄ (115 mg, 0.1 mmol) in dioxane (2 mL) was stirred at 100°C. for 3 hours under argon atmosphere on microwave synthesizer. Thecrude product was purified by prep-HPLC (MeCN/10 mM NH₄HCO₃) to give4-methyl-3-(1,3-oxazol-2-yl)aniline (92 mg, 52%) as an oil. ES-MS m/z:175.2 [M +H]⁺. LC-MS Purity (254 nm): >99%; t_(R)=1.31 min.

A mixture of 2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3(20 mg, 0.110 mmol), 4-methyl-3-(1,3-oxazol-2-yl)aniline (15 mg, 0.086mmol) and HATU (49 mg, 0.13 mmol) in DMF/NMM (1 mL/0.1 mL) was stirredat room temperature for 12 hours. The reaction mixture was purified byreverse phase chromatography (MeCN/10 mM NH₄HCO₃) to give the titlecompound (5.0 mg, 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ10.29 (s, 1H), 8.55 (d, J=2.4 Hz, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 7.73(dd, J=8.4 Hz, 2.0 Hz, 1H), 7.44 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.90(d, J=0.8 Hz, 1H), 2.71 (s, 3H), 2.60 (s, 6H) . ES-MS m/z: 348.2 [M+H]⁺.HPLC: Purity (214 nm): 98.16%; t_(R)=9.05 min.

Example 28 PREPARATION OFN-[4-CHLORO-3-(1,3-OXAZOL-5-YL)PHENYL]-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A mixture of sodium 4-methylbenzene-1-sulfinate (8.9 g, 50 mmol), formicacid (11.5 g, 250 mmol), paraformaldehyde (4.5 g, 150 mmol) andformamide (9.0 g, 200 mmol) was heated at 90° C. for 16 hours, cooled toroom temperature and filtered. The resulting solid was washed with coldwater (2*30 mL), and dried in vacuo to give crudeN-[(4-methylbenzenesulfonyl)methyl]formamide (5 g, 47% as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ9.04 (s, 1H), 7.99 (s, 1H), 7.74 (d,J=8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.73 (d, J=6.8 Hz, 2H), 2.41 (s,3H). ES-MS m/z: 214.0 [M+H]⁺. LC-MS Purity (214 nm): >92%; t_(R)=1.34min.

To an ice cold solution of N-[(4-methylbenzenesulfonyl)methyl]formamide(4.5 g, 21.1 mmol), and Et₃N (8.5 g, 84.4 mmol) in anhydrous THF (30 mL)was added POCl₃ (6.6 g, 42.2 mmol) dropwise at −5° C. The reactionmixture was stirred for 2 hours, poured into ice-water (100 mL) andstirred for 30 minutes. The solid was filtered, washed with cold water(2*30 mL) and dried in vacuo to giveN-[(4-methylbenzenesulfonyl)methyl]carbonitrile (2 g, 48.5%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ7.86 (d, J=8.4 Hz, 2H), 7.56 (d,J=8.04 Hz, 2H), 5.58 (s, 2H), 2.46 (s, 3H). ES-MS m/z: 213.0 [M+NH₄ ⁺].LC-MS Purity (214 nm): >97%; t_(R)=1.66 min.

A mixture of N-[(4-methylbenzenesulfonyl)methyl]carbonitrile (1.85 g,9.5 mmol) and 2-chloro-5-nitrobenzaldehyde (9.5 mmol), K₂CO₃ (2.6 g,19.0 mmol) in MeOH (15 mL) was stirred at room temperature for 2 hours,and diluted with ethyl acetate (50 mL). The organic phase was washedwith water (2*30 mL), dried over Na₂SO₄, filter and concentrated. Theresidue was purified by silica gel column (EA/PE: 1/10) to give5-(2-chloro-5-nitrophenyl)-1,3-oxazole as a yellow solid (1.07 g, 50%).¹H NMR (400 MHz, MeOD-d₄) δ8.72 (d, J=2.0 Hz, 1H), 8.45 (s, 1H), 8.24(dd, J=2.4 Hz, 8.8 Hz ,1H), 7.99 (s, 1H), 7.85 (d, J=8.8 Hz, 1H). ES-MSm/z:224.9 [M+H⁺]. LC-MS Purity (214 nm): >93%; t_(R)=1.76 min.

A suspension of 5-(2-chloro-5-nitrophenyl)-1,3-oxazole (800 mg, 3.6mmol), Fe powder (806 mg, 14.4 mmol), and NH₄Cl (1.56 g, 28.8 mmol) inMeOH/H₂O (3:2, 15 mL) was stirred at 80° C. for 2 hours, cooled to roomtemperature and filtered. The filtrate was concentrated, extracted withethyl acetate, dried over anhydrous Na₂SO₄, and concentrated in vacuo.The residue was purified by silica gel column (EA/PE: 1/3) to give4-chloro-3-(1,3-oxazol-5-yl)aniline (500 mg, 72%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ8.50 (s, 1H), 7.69 (s, 1H), 7.20 (d, J=9.2 Hz,1H), 7.03 (d, J=2.8 Hz, 1H), 6.60 (dd, J=2.8 Hz, 8.8 Hz, 1H), 5.50 (s,2H). LC-MS m/z: 195.1 [M+H⁺]. LC-MS Purity (214 nm): >95%; t_(R)=1.58min.

To a stirring solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (38 mg, 0.2mmol), HATU (152 mg, 0.4 mmol), and DIPEA (103 mg, 0.8 mmol) in 1 mL ofDMF was added 4-chloro-3-(1,3-oxazol-5-yl)aniline (46.6 mg, 0.24 mmol).The reaction mixture was stirred at room temperature for 3 days, andfiltered. The resulting solid was washed with H₂O, DCM and diethylether, and dried in vacuo to give the title compound (46.5 mg, 63%) as ayellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ10.42 (s, 1H), 8.61 (s, 1H),8.52 (s, 1H), 8.48 (s, 1H), 7.83 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.57(d, J=8.0 Hz, 1H), 6.90 (s, 1H), 2.71 (s, 3H), 2.60 (s, 3H). ES-MS m/z:368.0 [M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=9.05 min.

Example 29 PREPARATION OFN-(2-METHYL-1,3-BENZODIOXOL-6-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 2-methyl-1,3-benzoxazol-6-amine (47 mg, 0.314 mmol) and HATU (149g, 0.393 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.524 mmol), andthe reaction mixture was stirred at room temperature for 16 hours untilthe reaction was complete. The suspension was diluted with H₂O (3 mL),and the precipitated solid was collected by filtration, washed withminimum DCM and Et₂O, and dried in vacuo to give the title compound (57mg, 68%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.39 (s, 1H),8.48 (s, 1H), 8.36 (s, 1H), 7.60 (s, 2H), 6.90 (d, J=1.2 Hz, 1H), 2.71(s, 3H), 2.61 (s, 3H), 2.60 (s, 3H). ES-MS m/z: 322.0 [M+H]⁺. HPLCPurity (214 nm): >98%; t_(R)=8.17 min.

Example 30 PREPARATION OF 2,4-DIMETHYL-N-[2-(PYRIDIN-4-YL)-1,3-BENZOXAZOL-5-YL]IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of pyridine-4-carboxylic acid (1.2 g, 10 mmol),HATU (5.7 g, 15 mmol), and DIPEA (2.5 g, 20 mmol) in 12 mL of DMF wasadded 2-amino-4-nitrophenol (1.8 g, 12 mmol). The reaction mixture wasstirred at room temperature for 16 hours. The solid was filtered off,washed with H₂O, DCM and diethyl ether and dried to giveN-(2-hydroxy-5-nitrophenyl)pyridine-4-carboxamide as a brown solid (2 g,77.2%). ¹H NMR (400 MHz, DMSO-d₆) δ11.64 (s, 1H), 10.02 (s, 1H), 8.80(d, J=6.0 Hz, 2H), 8.70 (d, J=2.8 Hz, 1H), 8.04 (dd, J=2.8 Hz, 8.8 Hz,1H), 7.88 (dd, J=1.2 Hz, 6.0 Hz, 2H), 7.11(d, J=8.8 Hz, 1H) ES-MS m/z:260 [M+H]⁺. LC-MS Purity (254 nm): >98%; t_(R)=1.27 min.

A mixture of N-(2-hydroxy-5-nitrophenyl)pyridine-4-carboxamide (1 g,3.86 mmol) and TsOH.H₂O (690 mg, 3.86 mmol) in xylene was heated underreflux for 16 hours. Then, the reaction mixture was cooled with ice, andethyl acetate and 10% K₂CO₃ solution were added. The organic layer wasseparated, washed with H₂O and brine and dried over anhydrous Na₂SO₄.The resulting solution was concentrated in vacuo and the residue wastriturated with a mixture of n-hexane/diethyl ether (4/1). The solid wasfiltered and dried in vacuo to give5-nitro-2-(pyridin-4-yl)-1,3-benzoxazole (640 mg, 68%). ES-MS m/z: 242[M+H]⁺. LC-MS Purity (214 nm): >92%; t_(R)=1.51 min.

The solution of 5-nitro-2-(pyridin-4-yl)-1,3-benzoxazole (840 mg, 3.49mmol) and 10% Pd/C (200 mg) in EA/EtOH (1/1, 50 mL) was stirred at roomtemperature for 5 hours under H₂. Then, the reaction mixture wasfiltered, and the filtrate was concentrated and precipitated in EtO₂ togive 5-amino-2-(pyridin-4-yl)-1,3-benzoxazole (580 mg, 78.8%). ES-MSm/z: 211 [M+H]⁺. LC-MS Purity (214 nm): >98%; t_(R)=1.42 min.

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 5-amino-2-(pyridin-4-yl)-1,3-benzoxazole (61 mg, 0.288 mmol) andHATU (129 mg, 0.341 mmol) in DMF (1 mL) was added DIPEA (0.1 mL, 0.582mmol), and the reaction mixture was stirred at room temperature for 16hours until the reaction was complete. The suspension was diluted withH₂O (3 mL), and the precipitated solid was collected by filtration,washed with minimum DCM and Et₂O, and dried in vacuo to give the titlecompound (71 mg, 71%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ10.42(s, 1H), 8.85 (d, J=6.8 Hz, 2H), 8.49-8.48 (m, 2H), 8.11 (d, J=6.8 Hz,2H), 7.86-7.84 (m, 2H), 6.91 (s, 1H), 2.89 (s, 3H), 2.72 (s, 3H). ES-MSm/z: 385.2 [M+H]⁺. HPLC Purity (214 nm): 98%; t_(R)=8.13 min.

Example 31 PREPARATION OFN-{4-CHLORO-3-┌(PYRIDIN-3-YLOXY)METHYL┐PHENYL}-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

2—Chloro-5-nitrobenzaldeyhde (10 g, mmol) was dissolved in 150 ml ofMeOH and cooled to 0° C. A solution of NaBH₄ (3.33 g, mmol) in 30 ml ofwater was then added dropwise over 90 minutes while maintaining thetemperature below 10° C. The resultant reaction mixture was then stirredfor one hour, acidified with 2N HCl and left to stir overnight. Then,the mixture was concentrated in vacuo, and the resulting solids werefiltered then washed with water and dried in vacuo to give(2-chloro-5-nitrophenyl)methanol (9.3 g, 92%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ8.35 (d, J=2.8 Hz, 1H), 8.14 (dd, J=8.8 Hz, 2.8 Hz,1H), 7.73 (d, J=8.8 Hz, 1H), 5.81 (bs, 1H), 4.63 (s, 2H). LC-MS Purity(254 nm): >98%; t_(R)=1.60 min.

To an ice cold solution of (2-chloro-5-nitrophenyl)methanol (1.82 g, 9.8mmol) in DCM (60 mL) was added PPh₃ (2.62 g, 10 mmol), followed by CBr₄(3.26 g, 9.8 mmol). The reaction mixture was stirred at room temperaturefor 24 hours, and then diluted with DCM, washed with water and saturatedbrine solution. The organic layer was separated, dried (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by silicagel column (EA/PE: 1/10) to afford2-(bromomethyl)-1-chloro-4-nitrobenzene (1.56 g, 64%). ¹H NMR (400 MHz,DMSO-d₆) δ8.35 (d, J=2.8 Hz, 1H), 8.13 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.59(d, J=8.8 Hz, 1H), 4.62 (s, 2H). LC-MS Purity (254 nm): >80%; t_(R)=1.95min.

To an ice cold suspension of NaH (60%, 110 mg, 2.75 mmol) in anhydrousDMF (1 mL) was added dropwise the solution of 3-hydroxypyridine (250 mg,2.65 mmol) in DMF (2 mL. After the mixture was stirring at 0° C. for 15minutes, a solution of 2-(bromomethyl)-1-chloro-4-nitrobenzene (610 mg,2.45 mmol) in DMF (4 mL) was added dropwise. The reaction mixture wasstirred at 0° C. for another hour, quenched with water, and thenpartitioned between ethyl acetate and water. The organic layer wasseparated, washed with brine solution, dried over anhydrous (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by silicagel column (EA/PE: 1/1) to afford3-[(2-chloro-5-nitrophenyl)methoxy]pyridine (350 mg, 54%) as a creamsolid. ¹H NMR (400 MHz, DMSO-d₆) δ8.50 (d, J=2.8 Hz, 1H), 8.45 (d, J=2.8Hz, 1H), 8.32 (dd, J=4.8 Hz, 1.2 Hz, 1H), 8.18 (dd, J=8.8 Hz, 2.8 Hz,1H), 7.61 (d, J=8.8 Hz, 1H), 7.36-7.33 (m, 1H), 7.30-7.26 (m, 1H), 5.26(s, 2H). ES-MS m/z: 265 (M+H⁺). LC-MS Purity (254 nm): >97%; t_(R)=1.80min.

To a suspension of 3-[(2-chloro-5-nitrophenyl)methoxy]pyridine (320 mg,1.212 mmol) and NH₄Cl (513 mg, 9.696 mmol) in 9 mL of EtOH and 6 mL ofH₂O was added Fe powder (272 mg, 4.85 mmol) in portions. The reactionmixture was stirred at 80° C. for 3 hours, cooled down to roomtemperature and then filtered through Celite. The filter cake was washedwith EtOH. The orange solution was concentrated in vacuo, and theresidue was dissolved in DCM, then washed with saturated NaHCO₃. Theorganic phase was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by silica gel column (EA/PE: 3/1) toafford 4-chloro-3-[(pyridin-3-yloxy)methyl)]aniline (167 mg, 59%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.41 (dd, J=2.8 Hz, 0.8 Hz,1H), 8.25 (d, J=4.4 Hz, 2.0 Hz, 1H), 7.26-7.23 (m, 2H), 7.26 (d, J=8.4Hz, 1H), 6.59 (dd, J=8.4 Hz, 2.8 Hz, 1H), 5.13 (s, 2H), 3.71 (bs, 2H).

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (50 mg, 0.262mmol), 4-chloro-3-[(pyridin-3-yloxy)methyl)]aniline (67 mg, 0.288 mmol)and HATU (129 mg, 0.341 mmol) in DMF (1 mL) was added DIPEA (0.1 mL,0.524 mmol), and the reaction mixture was stirred at room temperaturefor 16 hours until the reaction was complete. Then, the suspension wasdiluted with H₂O (3 mL), and the precipitated solid was collected byfiltration, washed with minimum DCM and Et₂O, and dried in vacuo to givethe title compound (65 mg, 61%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ10.35 (s, 1H), 8.47 (s, 1H), 8.41 (d, J=3.2 Hz, 1H), 8.22 (dd,J=4.8 Hz, 1.2 Hz, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.88 (dd, J=8.4 Hz, 2.4Hz, 1H), 7.53-7.48 (m, 2H), 7.38 (dd, J=8.4 Hz, 4.8 Hz, 1H), 6.90 (s,1H), 5.24 (s, 2H), 2.70 (s, 3H), 2.58 (s, 3H). ES-MS m/z: 407.9 [M+H]⁺.HPLC Purity (214 nm): 98%; t_(R)=8.12 min.

Example 32 PREPARATION OF2,4-DIMETHYL-N-└4-(PENTYLOXY)PHENYL┘IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (38 mg, 0.2mmol), HATU (152 mg, 0.4 mmol), and DIPEA (103 mg, 0.8 mmol) in 2 mL ofDMF was added 4-(pentyloxy)aniline (43.0 mg, 0.24 mmol). The reactionmixture was stirred at 60° C. for 16 hours, and then the crude productwas purified by prep-HPLC (MeCN/10 mM NH₄HCO₃) to give the titlecompound (18.7 mg, 27%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ10.05 (s, 1H), 8.45 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz,2H), 6.88 (s, 1H), 3.95 (t, J=6.8 Hz, 2H), 2.70 (s, 3H), 2.59 (s, 3H),1.72 (t, J=7.2 Hz, 2H), 1.39 (m, 4H), 0.91 (t, J=7.2 Hz, 3H). ES-MS m/z:353.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.75 min.

Example 33 PREPARATION OF2,4-DIMETHYL-N-(6-(THIOPHEN-2-YL)PYRIDIN-3-YL)IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

A flask charged with 6-bromopyridin-3-amine (346 mg, 2.0 mmol),(thiophen-2-yl)boronic acid (307 mg, 2.4 mmol), Pd(dppf)Cl₂.CH₂Cl₂ (173mg, 0.2 mmol) and saturated NaHCO₃ solution (2 mL) was purged withnitrogen followed by the addition of 1,4-dioxane (6 mL). The mixture wasstirred and heated to 100° C. for one hour, then the mixture was cooledto room temperature, and filtered. The filtrate was extracted with ethylacetate, and washed with saturated brine. The combined organic phaseswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column (PE/EA=1/1) to give6-(thiophen-2-yl)pyridin-3-amine (327 mg, 92.8%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ8.07 (d, J=2.0 Hz, 1H), 7.47 (d, J=8.4 Hz, 1H),7.39 (dd, J=1.2 Hz, 4.0 Hz, 1H), 7.27 (dd, J=1.2 Hz, 5.2 Hz, 1H),7.07-7.05 (m, 1H), 6.99 (dd, J=2.8 Hz, 8.8 Hz, 1H). ES-MS m/z: 177[M+H]⁺. LC-MS Purity (214 nm): >97%; t_(R)=1.53 min.

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (40 mg, 0.21mmol), HATU (120 mg, 0.32 mmol), and DIPEA (54 mg, 0.42 mmol) in 1 mL ofDMF was added 6-(thiophen-2-yl)pyridin-3-amine (44 mg, 0.25 mmol). Thereaction mixture was stirred at room temperature for 2 days. Then, thesuspension was diluted with H₂O (2 mL), and the precipitated solid wascollected by filtration, washed with minimum DCM and Et₂O, and dried invacuo to give the title compound (22.1 mg, 30.1%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ10.41 (s, 1H), 8.95 (d, J=2.8 Hz, 1H), 8.49 (s,1H), 8.35 (dd, J=2.4 Hz, 8.4 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.71 (dd,J=0.4 Hz, 3.2 Hz, 1H), 7.57 (dd, J=0.8 Hz, 5.2 Hz, 1 H), 7.15 (dd, J=3.6Hz, 5.2 Hz, 1H), 6.91 (d, J=0.8 Hz, 1H), 2.72 (s, 3H), 2.60 (s, 3H).ES-MS m/z: 350.1 [M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=8.93 min.

Example 34 PREPARATION OFN-(4-(FURAN-2-YL)PHENYL)-5,7-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (38 mg, 0.20mmol) and HATU (99 mg, 0.26 mmol), in 1 mL of DMF was added DIPEA (52mg, 0.40 mmol), followed by the addition of 4-(furan-2-yl)aniline (35mg, 0.22 mmol). The reaction mixture was stirred at room temperature for16 hours until the reaction was complete and diluted with H₂O. The solidwas collected by filtration, washed with H₂O, DCM and diethyl ether, anddried in vacuo to give the title compound (42 mg, 63%) as a yellowsolid. 1H NMR (400 MHz, DMSO-d₆) δ10.30 (s, 1H),8.47 (s, 1H), 7.88 (d,J=8.8 Hz, 2H), 7.72-7.68 (m, 3H), 6.90 (s, 1H), 6.86 (d, J=3.2 Hz, 1H),6.58 (dd, J=3.2 Hz, 1.6 Hz, 1H), 2.71 (s, 3H), 2.61 (s, 3H). ES-MS m/z:333.1 [M+H]⁺. HPLC Purity (254 nm): 95%; t_(R)=7.68 min.

Example 35 PREPARATION OFN-(6-(FURAN-2-YL)PYRIDIN-3-YL)-2,4-DIMETHYLIMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE

To a stirred solution of2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid 3 (40 mg, 0.21mmol), HATU (120 mg, 0.32 mmol), and DIPEA (54 mg, 0.42 mmol) in 1 mL ofDMF was added 6-(furan-2-yl)pyridin-3-amine (40 mg, 0.25 mmol). Thereaction mixture was stirred at room temperature for 16 hours. Then, thesuspension was diluted with H₂O (2 mL), and the precipitated solid wascollected by filtration, washed with minimum DCM and Et₂O, and dried invacuo to give the title compound (41.2 mg, 58.8%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆) δ10.43 (s, 1H), 9.01 (d, J=2.4 Hz, 1H), 8.49 (s,1H), 8.37 (dd, J=2.8 Hz, 8.8 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H), 7.73 (d,J=8.4 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 6.91 (d, J=0.4 Hz, 1H), 6.64 (dd,J=1.6 Hz, 3.2 Hz, 1H), 2.71 (s, 3H), 2.60 (s, 3H). ES-MS m/z: 334.1[M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=8.21 min.

Example 36 ADDITIONAL IMIDAZO[1,5-a]PYRIMIDINE-8-CARBOXAMIDE COMPOUNDS

Using the general procedures described in Part I below, additionalimidazo[1,5-a]pyrimidine-8-carboxamide compounds were prepared. Theseaddition imidazo[1,5-a]pyrimidine-8-carboxamide compounds prepared arelisted in Part II below.

Part I—General Procedures

General Procedure A: Preparation of Amide by Coupling of a CarboxylicAcid Compound with an Amine Compound

To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU(1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (˜4 mL/0.2mmol) was added amine compound (1.25-2.0 equivalents). The reactionmixture was stirred at room temperature for 4-16 hours, and then washedwith saturated aqueous NaHCO₃ solution (5 mL/0.2 mmol), aqueous citricacid solution (5 mL/0.2 mmol) and brine (5 mL/0.2 mmol). The combinedextracts were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The resulting crude material was purified by silica gel columnchromatography or preparatory HPLC to give the amide compound.

General Procedure B: Conversion of Carboxylic Ester Compound toCarboxylic Acid Compound

To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents)and the mixture was heated at 80° C. for 2 hours and then concentrated.To the concentrate, 6N HCl solution was added to adjust the pH to 5-6and then the mixture was stirred for 10 minutes and subsequentlyfiltered. The resulting solid was collected and dried to give thecarboxylic acid compound.

General Procedure C: Preparation of Amide from a Carboxylic AcidCompound and Amine Compound

To a solution of carboxylic acid compound (1.0 equivalent) in DCM (3mL/0.5 mmol) was added DMF (1 drop) and oxalyl chloride (2.0equivalents). The solution was stirred at room temperature for 30minutes and then concentrated in vacuo. The resulting residue wasdissolved in DCM (1 mL/0.5 mmol) followed by the addition of aminecompound (5.0 equivalents) and triethylamine (2.0 equivalents). Thereaction mixture was stirred at RT for 2 hours and then diluted with DCM(10 mL/0.5 mmol). The organic solution was washed sequentially with H₂O(10 mL/0.5 mmol) and brine (10 mL/0.5 mmol), then dried over anhydrousNa₂SO₄, and next filtered. The filtrate was concentrated in vacuo, andthe resulting residue was purified by preparatory HPLC or silica gelchromatography to give the amide compound.

Part II—Compounds Prepared Following General Procedures

The following compounds were prepared based on the general proceduresdescribed in Part I above.

2,4-Bis(Difluoromethyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,5-a]pyrimidine-8-carboxamide

To a solution of ethyl2,4-bis(difluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (180 mg,0.62 mmol) in DCM (5 mL) was added BBr₃ (1M in DCM, 62 mL, 62 mmol) at0° C. The reaction mixture was stirred at −10° C. for 1 h and allowed tostir at 25° C. for 16 h. Then, the reaction mixture was poured into icewater and extracted with DCM (10 mL×3). The aqueous layer waslyophilized and the resulting residue was triturated in EtOAc (20 mL)and filtered. The filtrate was concentrated in vacuo to give2,4-bis(difluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid (150mg, 90%) as a yellow solid. LC-MS m/z: 263.0 [M+H]⁺. LC-MS Purity (214nm): >88%; t_(R)=1.08 min.

Following general procedure A,2,4-bis(difluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid (52mg, 0.2 mmol) and 1,2,3,4-tetrahydronaphthalen-1-amine afforded 2,4-thetitle compound (15.8 mg, 20%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): 6 8.29 (s, 1H), 7.67 (d, J=8.4 Hz, 1H), 7.40 (d, J=7.6 Hz, 1H),7.23 (s, 1H), 7.21-7.13 (m, 3H), 6.89-6.53 (m, 2H), 5.53-5.48 (m, 1H),2.98 (s, 2H), 2.23-2.16 (m, 2 H), 1.99-1.88 (m, 2H). LC-MS m/z: 392.1[M+H]⁺. HPLC: Purity (214 nm): >81%; t_(R)=8.19 min.

2-Cyclopropyl-N-(5,8-difluoro-4-methylchroman-4-yl)-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

To a suspension of Na (2.25 g, 97.8 mmol) in anhydrous toluene (30 mL)was added methyl 2-methoxyacetate (8.5 g, 81.5 mmol) at −5° C. Afterstirring for 3 h, cyclopropyl methyl ketone (7.2 g, 85.0 mmol) wasslowly added and the reaction mixture was stirred at RT overnight,acidified with 20% H₂SO₄ to pH˜4, and extracted with Et₂O (50 mL×3). Theorganic phases were dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo, and the residue was purified byflash chromatography column (0-20% EA in PE) to obtain1-cyclopropyl-4-methoxybutane-1,3-dione as a light yellow oil (5.6 g,44%), GCMS purity: >95%, GC-MS: m/z: 156.0 [M].

To a mixture of ethyl 5-amino-1H-imidazole-4-carboxylate (778 mg, 5.02mmol) in HOAc (15 mL) was added obtain1-cyclopropyl-4-methoxybutane-1,3-dione (1.57 g, 10.04 mmol) at 110° C.The reaction mixture was stirred at this temperature for 30 min, andconcentrated in vacuo. The residue was purified by reverse phasechromatography (MeCN/10 mM NH₄HCO₃) to give ethyl4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate(280 mg) (structure confirmed by NOESY) and ethyl2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate(200 mg) as yellow solids. 4-cPr: ¹H NMR (400 MHz, CDCl₃) δ8.28 (s, 1H),6.77 (d, J=0.8 Hz, 1H), 4.63 (s, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.48 (s,3H), 2.21-2.16 (m, 1H), 1.46 (t, J=7.2 Hz, 3H), 1.35-1.30 (m, 2H),1.06-1.02 (m, 2H).

Following general procedure B, ethyl2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate(194 mg, 0.70 mmol) afforded2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid sodium salt (240 mg, 32%). LC-MS m/z: 248.1 [M+H]⁺.

Following general procedure A,2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (37 mg, 0.15 mmol) and 5,8-difluoro-4-methylchroman-4-amineafforded the title compound (21 mg, 33%) as a yellow solid. ¹H NMR (500MHz, MeOD-d₄) δ8.75 (s, 1H), 8.23 (s, 1H), 7.05-7.03 (m, 2H), 6.65-6.58(m, 1H), 4.84 (s, 2H), 4.41-4.37 (m, 1H), 4.28-4.23 (m, 1H), 3.51 (s,3H), 3.24-3.18 (m, 1H), 2.23-2.18 (m, 1H), 2.14-2.09 (m, 1H), 1.94 (s,3H), 1.19-1.13 (m, 3H), 1.01-0.97 (m, 1H) LC-MS m/z: 429.2 [M+H]⁺. HPLC:Purity (214 nm): >95%; t_(R)=9.81 min.

4-Methyl-N-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)-2-(trifluoromethy)imidazo[1,5-a]pyrimidine-8-carboxamide

Ethyl 5-amino-1H-imidazole-4-carboxylate (600 mg, 3.87 mmol) and1,1,1-trifluoropentane-2,4-dione (655 mg, 4.25 mmol) in AcOH (10 mL) wasstirred at 100° C. for 2 h until the reaction was complete (LC-MS). Thereaction mixture was concentrated in vacuo and the residue was purifiedby silica gel column (PE/EA: 2/1) to obtain ethyl4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (220mg, 20%) as a white solid. LC-MS m/z: 274.1 [M+H]⁺. LC-MS purity (214nm): 83%; t_(R)=1.68 min.

To a stirred solution of bis(tributyltin) oxide (0.75 mL, 1.46 mmol) intoluene (10 mL) was added ethyl4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (200mg, 0.73 mmol). The mixture was refluxed for 24 h and the solvent wasevaporated in vacuo. The resulting oil was dissolved in EtOAc (10 mL)and washed with 5% aqueous NaHCO₃ (3×5 mL). The aqueous phase wasacidified to pH 4-5 with dilute HCl and concentrated in vacuo to afford4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(100 mg, 50%) as a pale white solid. LC-MS m/z: 246.0 [M +H]⁺. LCMS:Purity (214 nm): 83%; t_(R)=1.06 min.

Following general procedure A,4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(20 mg, 0.08 mmol) and 1-methyl-1,2,3,4-tetrahydronaphthalen-1-amineafforded the title compound (4 mg, 13%) as a yellow solid. ¹H NMR (500MHz, CDCl₃) δ8.06 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.59 (dd, J=7.5 Hz,1.0 Hz, 1H), 7.24-7.12 (m, 3H), 6.96 (s, 1H), 2.93-2.88 (m, 2H),2.84-2.80 (m, 1H), 2.67 (s, 3H), 2.09-2.03 (m, 2H), 1.92 (s, 3H),1.93-1.85 (m, 2H). LC-MS m/z: 389.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.57 min.

(S)-4-isoPropyl-2-methyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1.5-a]pyrimidine-8-carboxamide(LTI-457)

A mixture of 3-methylbutan-2-one (5.0 g, 58 mmol) and EtOAc (5.35 g, 175mmol) in THF (50 mL) was added dropwise to a solution of t-BuOK (9.75 g,87 mmol) in THF (130 mL) at 60° C. After addition, the reaction mixturewas stirred at 60° C. for 4 h, cooled to RT and quenched with HCl (2M,60 mL). The aqueous layer was separated, extracted with EtOAc (50 mL×3)and the combined organic phases were dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the residue waspurified by silica gel chromatography (PE/EA=10:1) to give5-methylhexane-2,4-dione (2.6 g, 35%) as a yellow oil.

To a stirred solution of 5-methylhexane-2,4-dione (3.1 g, 20 mmol) inAcOH (40 mL) was added ethyl 5-amino-1H-imidazole-4-carboxylate (1.9 g,24 mmol). The reaction mixture was stirred at 100° C. for 6 hours andconcentrated in vacuo. The residue was purified by silica gel column(DCM/MeOH: 1/0 to 10/1) to give ethyl2-isopropyl-4-methylimidazolo[1,5-a]pyrimidine-8-carboxylate (1.2 g,40%) as a yellow solid. LC-MS m/z: 248.1 [M+H]⁺. LC-MS Purity (214nm): >80%; t_(R)=1.63 min.

Following general procedure B, ethyl2-isopropyl-4-methylimidazolo[1,5-a]pyrimidine-8-carboxylate (1.15 g,4.65 mmol) afforded2-isopropyl-4-methylimidazolo[1,5-a]pyrimidine-8-carboxylic acid (960mg, 90%) as a yellow solid. LC-MS m/z: 220.1 [M+H]⁺. LC-MS Purity (214nm): >97%; t_(R)=1.12 min.

Following general procedure A,2-isopropyl-4-methylimidazolo[1,5-a]pyrimidine-8-carboxylic acid (40 mg,0.18 mmol) and (5)-1,2,3,4-tetrahydronaphthalen-1-amine afforded thetitle compound (28 mg, 45%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄): δ8.58 (d, J=9.0 Hz, 1H), 8.31 (s, 1H), 7.23 (d, J=7.5 Hz, 1H),7.07-7.00 (m, 3H), 6.67(s, 1H), 5.27-5.25 (m, 1H), 3.38-3.33 (m, 1H),2.83-2.78 (m, 1H), 2.75-2.69 (m, 1H), 2.39 (s, 3H), 2.10-2.05 (m, 1H),1.92-1.79 (m, 3H), 1.33 (d, J=7.0 Hz, 6H). LC-MS m/z: 349.2 (M+H)⁺. HPLCPurity (214 nm): >99%; t_(R)=8.34 min.

2,4-Dimethyl-N-(1-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (38 mg, 0.2 mmol)and 1-methyl-1,2,3,4-tetrahydronaphthalen-1-amine afforded the titlecompound (45 mg, 67%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ8.01(s, 1H), 7.88 (s, 1H), 7.63 (d, J=7.6 Hz, 1H), 7.22-7.10 (m, 3H), 6.45(s, 1H), 2.93-2.87 (m, 2H), 2.83-2.77 (m, 1H), 2.62 (s, 3H), 2.52 (s,3H), 2.12-2.06 (m, 1H), 1.90 (s, 3H), 1.94-1.82 (m, 2H). LC-MS m/z:335.2 [M+H]⁺. HPLC: purity (214 nm): >99%; t_(R)=7.95 min.

N-(8-Fluoro-4-methylchroman-4-yl)-4-isopropyl-2-methylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-isopropyl-2-methylimidazo[1,5-a]pyrimidine-8-carboxylic acid (36 mg,0.16 mmol) and 8-fluoro-4-methylchroman-4-amine afforded the titlecompound (8 mg, 13%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄): δ8.41(s, 1H), 7.34 (d, J=7.5 Hz, 1H), 7.04-7.00 (m, 1H), 6.93-6.90 (m, 1H),6.81 (s, 1H), 4.41-4.31 (m, 2H), 3.51-3.45 (m, 1H), 3.11-3.06 (m, 1H),2.52 (s, 3H), 2.26-2.21 (m, 1H), 1.92 (s, 3H), 1.46 (d, J=7.0 Hz, 3H),1.45 (d, J=7.0 Hz, 3H). LC-MS m/z: 383.2 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=8.17 min.

2,4-Dimethyl-N-(6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl-5-d)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,7-methyl-5-methylimidazo[1,5-a]pyrimidine-3-carboxylic (1.12 g, 5.81mmol) and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-d-5-amine afforded thetitle compound (1.1 g, 48%) as a white solid. ¹H NMR (500 MHz, CDCl₃):δ8.60 (s, 1H), 7.96 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.14 (m, 3H), 6.48(s, 1H), 3.14-3.10 (m, 1H), 2.96-2.91 (m, 1H), 2.64 (s, 3H), 2.59 (s,3H), 2.12-1.90 (m, 4H), 1.74-1.71 (m, 2H). LC-MS m/z: 336.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=7.90 min.

N-(2-(4-Ethynylphenyl)propan-2-yl)-4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(20 mg, 0.102 mmol) and 2-(4-ethynylphenyl)propan-2-amine afforded thetitle compound (5 mg, 17%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄):δ8.37 (s, 1H), 7.61 (s, 1H), 7.42 (s, 4H), 4.13 (s, 1H), 2.62 (s, 3H),1.72 (s, 6H). LC-MS m/z: 387.1 [M+H]⁺. HPLC Purity (214 nm): 95%;t_(R)=8.27 min.

N-(2-(3-Ethynylphenyl)propan-2-yl)-4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-methyl-2-(trifluoromethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(20 mg, 0.08 mmol) and 2-(3-ethynylphenyl)propan-2-amine afforded thetitle compound (5 mg, 17%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄):δ8.39 (d, J=1.5 Hz, 1H), 7.62 (s, 1H), 7.59-7.56 (m, 1H), 7.54 (dt,J=7.0 Hz, 2.0 Hz, 1H), 7.49-7.46 (m, 1H), 7.36-7.31 (m, 2H), 3.45 (s,1H), 2.72 (s, 3H), 1.85 (s, 6H). LC-MS m/z: 387.1 [M+H]⁺. HPLC Purity(214 nm): >99%; t_(R)=8.27 min.

N-(2-(3-Ethynylphenyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (48 mg, 0.25 mmol)and 2-(3-ethynylphenyl)propan-2-amine afforded the title compound (42mg, 45%) as a white solid. ¹H NMR(500 MHz, CDCl₃): δ8.25 (s, 1H), 7.91(s, 1H), 7.66 (t, J=1.0 Hz, 1H), 7.53 (dt, J=8.0 Hz, 1.0 Hz, 1H), 7.33(dt, J=8.0 Hz, 1.0 Hz, 1H), 7.28-7.24 (m, 1H), 6.49 (d, J=1.0 Hz, 1H),3.02 (s, 1H), 2.62 (s, 3H), 2.57 (s, 3H), 1.86 (s, 6H). LC-MS m/z: 333.3[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.69 min.

N-(2-(4-Ethynylphenyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.204mmol) and 2-(4-ethynylphenyl)propan-2-amine afforded the title compound(42 mg, 53%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄): δ8.25 (s, 1H),7.48 (d, J=6.8 Hz, 2H), 7.41 (d, J=6.4 Hz, 2H), 6.77 (s, 1H), 3.43 (s,1H), 2.70 (s, 3H), 2.59 (s, 3H), 1.86 (s, 6H). LC-MS m/z: 333.2 [M+H]⁺.HPLC: Purity (214 nm): 92%; t_(R)=7.73 min.

N-(2-(4-Fluorophenyl)butan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (20 mg, 0.11mmol) and 2-(4-fluorophenyl)butan-2-amine afforded the title compound(15.4 mg, 45%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ8.26 (s,1H), 7.95 (s, 1H), 7.43-7.40 (m, 2H), 6.97 (t, J=9.0 Hz, 2H), 6.50 (d,J=1.0 Hz, 1H), 2.65 (d, J=0.5 Hz, 3H), 2.58 (s, 3H), 2.21-2.17 (m, 1H),2.09-2.05 (m, 1H), 1.79 (s, 3H), 0.89 (t, J=7.0 Hz, 3H). LC-MS m/z:341.2 [M+H]⁺. HPLC: Purity (214 nm): >97%; t_(R)=7.97 min.

4-isoPropyl-2-methyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-isopropyl-2-methylimidazolo[1,5-a]pyrimidine-8-carboxylic acid (40 mg,0.18 mmol) and (1R,4R)-4-(pentyloxy)cyclohexan-1-amine afforded thetitle compound (14 mg, 21%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃):δ8.02 (s, 1H), 7.82 (d, J=10.0 Hz, 1H), 6.48 (s, 1H), 4.11-4.07 (m, 1H),3.45 (t, J=8.5 Hz, 2H), 3.32-3.25 (m, 2H), 2.61 (s, 3H), 2.20-2.17 (m,2H), 2.07-2.04 (m, 2H), 1.61-1.51 (m, 2H), 1.49-1.37 (m, 7H), 1.34-1.26(m, 7H), 0.91 (d, J=8.5 Hz, 3H). LC-MS m/z: 387.2 [M+H]⁺. HPLC: Purity(214 nm): >99%; t_(R)=9.19 min.

N-(2,3-Dihydro-1H-inden-4-yl)-4-isopropyl-2-methylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure C,4-isopropyl-2-methylimidazolo[1,5-a]pyrimidine-8-carboxylic acid (40 mg,0.18 mmol) and 2,3-dihydro-1H-inden-4-amine afforded the title compound(23 mg, 38%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ9.97 (s, 1H),8.36 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 7.21 (t, J=7.0 Hz, 1H), 6.99 (d,J=7.5 Hz, 1H), 6.54 (s, 1H), 3.35-3.29 (m, 1H), 3.07 (t, J=7.0 Hz, 2H),2.99 (t, J=7.0 Hz, 2H), 2.67 (s, 3H), 2.20-2.14 (m, 2H), 1.48 (d,J=6.5Hz, 6H). LC-MS m/z: 335.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.81 min.

N-((1R,4R)-4-((4,4-Dimethylcyclohexyl)oxy)cyclohexyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (38 mg, 0.2 mmol)and (1R,4R)-4-((4,4-dimethylcyclohexyl)oxy)cyclohexan-1-amine affordedthe title compound (45.8 mg, 56%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ7.93 (s, 1H), 7.75 (d, J=7.6 Hz, 1H), 6.49 (s, 1H), 4.08-4.06(m, 1H), 3.41-3.39 (m, 1H), 3.34-3.29 (m, 1H), 2.64 (s, 3H), 2.59 (s,3H), 2.20-2.18 (m, 2H), 2.01-1.98 (m, 2H), 1.75-1.70 (m, 2H), 1.49-1.31(m, 8H), 1.21-1.14 (m, 2H), 0.92 (s, 3H), 0.90 (s, 3H). LC-MS m/z: 399.3[M+H]⁺. HPLC: Purity (214 nm): >95%; t_(R)=9.23 min.

N-((1S,3S)-3-(Hexyloxy)cyclopentyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (38 mg, 0.20mmol) and (1S,3S)-3-(hexyloxy)cyclopentan-1-amine afforded the titlecompound (20 mg, 28%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ7.93(s, 1H), 7.80 (d, J=7.0 Hz, 1H), 6.49 (d, J=1.0 Hz, 1H), 4.68-4.64 (m,1H), 4.07-4.03 (m, 1H), 3.40-3.35 (m, 2H), 2.64 (s, 3H), 2.60 (s, 3H),2.32-2.18 (m, 2H), 2.09-2.02 (m, 1H), 1.88-1.83 (m, 1H), 1.76-1.70 (m,1H), 1.63-1.53 (m, 3H), 1.36-1.28 (m, 6H), 0.90 (t, J=7.5 Hz, 3H); LC-MSm/z: 359.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.67 min.

N-(4-Ethynyl-2-fluorophenyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (30 mg, 0.16mmol) and 4-ethynyl-2-fluoroaniline afforded the title compound (2.8 mg,6%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ10.43 (s, 1H), 8.73 (t,J=8.5 Hz, 1H), 8.03 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.24 (s, 1H), 6.58(s, 1H), 3.06 (s, 1H), 2.69 (s, 3H), 2.67 (s, 3H). LC-MS m/z: 309.1[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.73 min.

N-(4-Ethynyl-3-fluorophenyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (30 mg, 0.16mmol) and 4-ethynyl-3-fluoroaniline afforded the title compound (1.3 mg,3%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃): δ10.43 (s, 1H), 8.73 (t,J=8.5 Hz, 1H), 8.03 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.24 (s, 1H), 6.58(s, 1H), 3.06 (s, 1H), 2.69 (s, 3H), 2.67 (s, 3H). LC-MS m/z: 309.1[M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=7.73 min.

4-Cyclopropyl-2-(methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure B, ethyl4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate(774 mg, 2.81 mmol) afforded4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (225 mg, 33%) as a white solid. LC-MS m/z: 248.1 [M+H]⁺.

Following general procedure A,4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (20 mg, 0.08 mmol) and 2-(3-propoxyphenyl)propan-2-amine affordedthe title compound (11.7 mg, 36%) as a yellow oil. ¹H NMR (500 MHz,CDCl₃): δ8.72 (s, 1H), 8.59 (s, 1H), 7.24 (t, J=8.0 Hz, 1H), 7.08-7.05(m, 2H), 6.80 (d, J=2.0 Hz, 1H), 6.78 (s, 1H), 4.57 (s, 2H), 3.91 (t,J=6.0 Hz, 2H), 3.49 (s, 3H), 2.45-2.42 (m, 1H), 1.86 (s, 6H), 1.79-1.75(m, 2H), 1.37-1.34 (m, 2H), 1.11-1.09 (m, 2H), 1.02 (t, J=7.5 Hz, 3H).LC-MS m/z: 423.3 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=10.51 min.

2-Cyclopropyl-4-(methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (37 mg, 0.15 mmol) and 2-(3-propoxyphenyl)propan-2-amine affordedthe title compound (21 mg, 33%) as a yellow solid. ¹H NMR (500 MHz,CDCl₃) δ8.31 (s, 1H), 8.03 (s, 1H), 7.25 (t, J=8.0 Hz ,1H), 7.11 (d,J=8.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 6.77 (dd, J=8.0 Hz, 2.0 Hz, 1H),6.68 (s, 1H), 4.71 (s, 2H), 3.92 (t, J=6.5 Hz, 2H), 3.54 (s, 3H),2.10-2.07 (m, 1H), 1.88 (s, 6H), 1.83-1.77 (m, 2H), 1.16-1.10 (m, 4H),1.04 (t, J=7.5 Hz, 3H). LC-MS m/z: 422.9 [M+H]⁺. HPLC: Purity (214nm): >94%; t_(R)=10.62 min.

2,4-bis(Methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamideand3-Methoxy-4-(methoxymethyl)-2-methyl-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide

To a solution of t-BuONa (3.3 g, 34.1 mmol) in 30 mL of anhydrous THFwas added sequentially dropwise methyl 2-methoxyacetate (2 g, 22.7 mmol)and 1-methoxypropan-2-one (7.1 g, 68.2 mmol). The reaction mixture wasstirred at 60° C. for 5 h, cooled and acidified with 2M HCl to pH ˜5.The mixture was extracted with EtOAc (30 mL×3) and the combined organicphases were washed with water (40 mL) and brine (40 mL), dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel column (PE/EA; 5:1) togive a mixture of 1,5-dimethoxypentane-2,4-dione and1,3-dimethoxypentane-2,4-dione (1.5 g, 41%,) as a yellow oil. LC-MS m/z:161.1 [M+H]⁺. LCMS: t_(R)=0.73 min.

To a solution of 1,5-dimethoxypentane-2,4-dione and1,3-dimethoxypentane-2,4-dione (800 mg, 5 mmol) in HOAc (10 mL) wasadded ethyl 5-amino-1H-imidazole-4-carboxylate (458 mg, 3.32 mmol) andthe mixture was stirred at 90° C. for 50 minutes and concentrated invacuo. The resulting residue was purified by silica gel chromatography(EA) to give ethyl2,4-bis(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate and ethyl3-methoxy-4-(methoxymethyl)-2-methylimidazo[1,5-a]pyrimidine-8-carboxylate(470 mg, 34%) as a yellow solid. LC-MS m/z: 280.0 [M+H]⁺. LC-MS:t_(R)=1.55 min.

Following general procedure B, ethyl2,4-bis(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate and ethyl3-methoxy-4-(methoxymethyl)-2-methylimidazo[1,5-a]pyrimidine-8-carboxylate(200 mg, 0.72 mmol) afforded a mixture of2,4-bis(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid and3-methoxy-4-(methoxymethyl)-2-methylimidazo[1,5-a]pyrimidine-8-carboxylicacid as yellow solids (80 mg, 44%). LC-MS m/z: 252.1 [M+H]⁺. LCMS:t_(R)=0.60 min.

Following general procedure A,2,4-bis(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid and3-methoxy-4-(methoxymethyl)-2-methylimidazo[1,5-a]pyrimidine-8-carboxylicacid (80 mg, 0.32 mmol) and 2-(3-propoxyphenyl)propan-2-amine affordedthe title compounds2,4-bis(methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide(23.3 mg, 17%) and3-methoxy-4-(methoxymethyl)-2-methyl-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide(25 mg, 18%) as brown oils.

2,4-bis(Methoxymethyl)-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide:¹H NMR (400 MHz, MeOD-d₄) δ8.31 (s, 1H), 7.21 (t, J=7.2 Hz, 1H), 7.13(s, 1H), 7.07-7.04 (m, 2H), 6.77 (dd, J=8.0 Hz, 1.6 Hz, 1H), 4.87 (s,2H), 4.60 (s, 2H), 3.89 (t, J=6.8 Hz, 2H), 3.51 (s, 3H), 3.49 (s, 3H),1.83 (s, 6H), 1.75 (q, J=7.2 Hz, 2H), 1.00 (t, J=7.2 Hz, 3H). LC-MS:m/z, 427.3 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=10.26 min.

3-Methoxy-4-(methoxymethyl)-2-methyl-N-(2-(3-propoxyphenyl)propan-2-yl)imidazo[1,5-a]pyrimidine-8-carboxamide:¹H NMR (400 MHz, MeOD-d₄) δ8.27 (s, 1H), 7.23 (t, J=8.0 Hz, 1H),7.07-7.04 (m, 2H), 6.78 (dd, J=8.4 Hz, 2.0 Hz, 1H), 4.95 (s, 2H), 3.90(t, J=8.0 Hz, 2H), 3.89 (s, 3H), 3.47 (s, 3H), 2.63 (s, 3H), 1.83 (s,6H), 1.78 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H). LC-MS: m/z, 427.3[M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=10.53 min.

N-(2-(3—Cyanophenyl)propan-2-yl)-4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (56 mg, 0.23 mmol) and 3-(2-aminopropan-2-yl)benzonitrile affordedthe title compound (16 mg, 18%) as a yellow oil. ¹H NMR (500 MHz,CDCl₃): δ8.25 (s, 1H), 8.09 (s, 1H), 7.78 (s, 1H), 7.74 (d, 8.0 Hz, 1H),7.48 (d, J=8.0 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 6.70 (s, 1H), 4.56 (s,2H), 3.47 (s, 3H), 2.18-2.14 (m, 1H), 1.84 (s, 6H), 1.34-1.30 (m, 2H),1.05-1.02 (m, 2H). LC-MS m/z: 390.0 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=9.34 min.

N-(2-(3-cyclopropoxyphenyl)propan-2-yl)-4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (20 mg, 0.08 mmol) and 2-(3-cyclopropoxyphenyl)propan-2-amineafforded the title compound (23.5 mg, 69%) as a yellow oil. ¹H NMR (500MHz, CDCl₃): δ8.22 (s, 1H), 8.06 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.17(d, J=2.0 Hz, 1H), 7.15 (td, J=8.0 Hz, 0.5 Hz, 1H), 6.97 (dd, J=8.0 Hz,2.0 Hz, 1H), 6.67 (s, 1H), 4.53 (s, 2H), 3.72-3.71 (m, 1H), 3.45 (s,3H), 2.15-2.13 (m, 1H), 1.87 (s, 6H), 1.31-1.29 (m, 2H), 1.02-1.00 (m,2H), 0.75-0.73 (m, 4H). LC-MS m/z: 421.3 [M+H]⁺. HPLC Purity (214nm): >98%; t_(R)=10.17 min.

N-(2-(3-Cyclopropoxyphenyl)propan-2-yl)-2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (37 mg, 0.15 mmol) and 2-(3-cyclopropoxyphenyl)propan-2-amineafforded the title compound (21 mg, 33%) as a yellow solid. ¹H NMR (500MHz, MeOD-d₄) δ8.69 (s, 1H), 8.23 (s, 1H), 7.26 (t, J=8.0 Hz, 1H),),7.13 (t, J=2.0 Hz, 1H), 7.09 (d, J=7.5 Hz 1H), 7.03 (s 1H), 6.98 (dd,J=8.0 Hz, 2.5 Hz, 2H), 4.85 (s, 1H),), 3.75-3.72 (m, 1H), 3.52 (s, 3H),2.25-2.22 (m, 1H), 1.85 (s, 6H), 1.22-1.19 (m, 2H), 1.55-1.13 (m, 2H),0.72-0.70 (m, 2H), 0.67-0.64 (m, 2H). LC-MS m/z: 421.3 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=9.81 min.

N-(2-(3-Cyclopropoxyphenyl)propan-2-yl)-4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

To a solution of sodium (1.43 g, 62.3 mmol) in toluene (30 mL) was addedmethyl 2-methoxyacetate (5.4 g, 51.92 mmol) at −5° C. After stirring for3 h, methyl isopropyl ketone (5.0 g, 58.67 mmol) was slowly added. Themixture was then stirred at RT overnight, quenched with saturated NH₄Cl(100 mL), and extracted with EtOAc (150 mL×3). The combined organicphases were dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EA=15:1) to afford 1-methoxy-5-methylhexane-2,4-dioneas a light yellow oil (2.5 g, 30%). ¹H NMR (500 MHz, CDCl₃): δ15.33 (bs,1H), 5.81 (s, 1H), 4.01 (s, 2H), 3.44 (s, 3H), 2.55-2.50 (m, 1H), 1.18(d, J=6.5 Hz, 6H).

To a stirred solution of ethyl 5-amino-1H-imidazole-4-carboxylate (1 g,6.45 mmol) in 2 mL of AcOH was added 1-methoxy-5-methylhexane-2,4-dione(1.2 g, 7.74 mmol) at 110° C. The reaction mixture was stirred at 110°C. for 1 h and concentrated in vacuo. The residue was purified by silicagel column and then by reverse phase chromatography to give ethyl4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (700mg, 39%) and ethyl2-isopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (105mg, 6%) as yellow solids (structure confirmed by NOESY). 4-iPr: ¹H NMR(400 MHz, CDCl₃): δ8.10 (s, 1H), 6.95 (s, 1H), 4.67 (s, 2H), 4.50 (q,J=7.2 Hz, 2H), 3.51 (s, 3H), 3.38-3.32 (m, 1H), 1.48 (d, J=6.4 Hz, 6H),1.46 (t, J=7.2 Hz, 3H), 2-iPr: ¹H NMR (400 MHz, CDCl₃): δ8.07 (s, 1H),6.77 (s, 1H), 4.72 (s, 2H), 4.50 (q, J=7.2 Hz, 2H), 3.51 (s, 3H),3.23-3.19 (m, 1H), 1.47 (t, J=7.2 Hz, 3H), 1.37 (d, J=7.2 Hz, 6H).

Following general procedure B, ethyl4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (700mg, 2.53 mmol) afforded4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(540 mg, 86%) as a yellow solid. LC-MS m/z: 250.1 [M+H]⁺. LC-MS Purity(214 nm): 82.3%; t_(R)=1.25 min.

Following general procedure A,4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(30 mg, 0.12 mmol) and 2-(3-cyclopropoxyphenyl)propan-2-amine affordedthe title compound (32.6 mg, 64%) as a yellow oil. ¹H NMR (500 MHz,CDCl₃): δ8.10 (s, 1H), 8.05 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.15 (t,J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 1H), 6.84 (s, 1H), 4.56 (s, 2H),3.72-3.70 (m, 1H), 3.47 (s, 3H), 3.32-3.29 (m, 1H), 1.87 (s, 6H), 1.47(d, J=7.0 Hz, 6H), 0.74-0.73 (m, 4H). LC-MS m/z: 423.3 [M+H]⁺. HPLCPurity (214 nm): >98%; t_(R)=10.39 min.

N-(2-(3-Cyclopropoxyphenyl)propan-2-yl)-2-isopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure B, ethyl2-isopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylate (105mg, 0.38 mmol) afforded2-isopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(60 mg, 64%) as a yellow solid. LC-MS m/z: 250.1 [M+H]⁺. LC-MS Purity(214 nm): 63.9%; t_(R)=1.25 min.

Following general procedure A,2-isopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(30 mg, 0.12 mmol) and 2-(3-cyclopropoxyphenyl)propan-2-amine affordedthe title compound (27.3 mg, 54%) as a yellow oil. ¹H NMR (500 MHz,CDCl₃): δ8.45 (s, 1H), 8.05 (s, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.16-7.13(m, 2H), 6.96 (dd, J=8.0 Hz, 1.5 Hz, 1H), 6.69 (s, 1H), 4.71 (s, 2H),3.71-3.69 (m, 1H), 3.51 (s, 3H), 3.10-3.07 (m, 1H), 1.87 (s, 6H), 1.30(d, J=7.0 Hz, 6H), 0.74-0.72 (m, 4H). LC-MS m/z: 423.3 [M+H]⁺. HPLCPurity (214 nm): >98%; t_(R)=10.70 min.

2-Cyclopropyl-N-(2-(3-ethoxymethyl)phenyl)propan-2-yl)-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide(LTv-706)

Following general procedure A,2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (35 mg, 0.14 mmol) and 2-(3-ethoxymethylphenyl)propan-2-amineafforded the title compound (7 mg, 12%) as a yellow solid. ¹H NMR (500MHz, MeOD-d₄) δ8.71 (s, 1H), 8.23 (s, 1H), 7.48 (s, 1H), 7.43 (d, J=7.5Hz, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.22 (d, J=6.0 Hz, 1H), 7.04 (s, 1H),4.85 (s, 2H), 4.51 (s, 2H), 3.53 (q, J=7.0 Hz, 2H), 3.52 (s, 3H),2.27-2.23 (m, 1H), 1.86 (s, 6H), 1.32-1.20 (m, 2H), 1.18 (t, J=7.0 Hz,3H), 1.16-1.13 (m, 2H). LC-MS m/z: 423.3 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.24 min.

N-(2-(3-(ethoxymethyl)phenyl)propan-2-yl)-4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-isopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid(30 mg, 0.12 mmol) and 2-(3-(ethoxymethyl)phenyl)propan-2-amine affordedthe title compound (46 mg, 90%) as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ8.10 (s, 1H), 8.06 (s, 1H), 7.46 (s, 1H), 7.45 (d, J=7.6 Hz,1H), 7.30 (t, J=7.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 6.84 (s, 1H), 4.56(s, 2H), 4.50 (s, 2H), 3.53 (q, J=6.8 Hz, 2H), 3.47 (s, 3H), 3.33-3.29(m, 1H), 1.88 (s, 6H), 1.47 (d, J=6.8 Hz, 6H), 1.22 (t, J=6.8Hz, 3H).LC-MS m/z: 425.3 [M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=10.15 min.

N-(2-(3-(ethoxymethyl)phenyl)propan-2-yl)-2-isopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2-cyclopropyl-4-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (30 mg, 0.12 mmol) and 2-(3-(ethoxymethyl)phenyl)propan-2-amineafforded the title compound (34 mg, 67%) as a yellow oil. ¹H NMR (400MHz, CDCl₃): δ8.47 (s, 1H), 8.06 (s, 1H),7.47 (s, 1H), 7.44 (d, J=7.6Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 6.70 (s, 1H),4.71 (s, 2H), 4.50 (s, 2H), 3.52 (t, J=7.2 Hz, 2H), 3.51 (s, 3H),3.12-3.06 (m, 1H), 1.88 (s, 6H), 1.31 (d, J=6.8 Hz, 6H), 1.21 (t, J=7.2Hz, 3H). LC-MS m/z: 423.3 [M+H]⁺. HPLC Purity (214 nm): >98%;t_(R)=10.70 min.

N-(2-((1R4R)-4-Methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamideandN-(2-((1R4S)-4-Methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (100 mg, 0.52mmol) and 2-(4-methoxycyclohexyl)propan-2-amine affordedN-(2-((1R4R)-4-methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamideas a pale white solid (19.8 mg, 11%) andN-(2-((1R4S)-4-methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide (32 mg, 8%) as a pale white solid.

N-(2((1R4R)-4-Methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide:¹H NMR (500 MHz, MeOD-d₄) δ8.34 (s, 1H), 8.03 (s, 1H), 6.81 (s, 1H),3.23 (s, 1H), 3.08-3.05 (m, 1H), 2.66 (s, 3H), 2.51 (s, 3H), 2.52-2.50(m, 1H), 2.08-2.06 (m, 2H), 1.84-1.82 (m, 2H), 1.36 (s, 6H), 1.18-1.07(m, 4H). LC-MS m/z: 345.2 [M+H]⁺. HPLC: Purity (254 nm): >99%;t_(R)=9.05 min.

N-(2-((1R4S)-4-Methoxycyclohexyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide:¹H NMR (500 MHz, MeOD-d₄) δ8.33 (s, 1H), 8.04 (s, 1H), 6.80 (s, 1H),3.20 (s, 3H), 2.66 (s, 3H), 2.66-2.64 (m, 1H), 2.53 (s, 3H), 1.96-1.92(m, 2H), 1.88-1.82 (m, 1H), 1.56-1.54 (m, 2H), 1.36 (s, 6H), 1.36-1.33(m, 4H). LC-MS m/z: 345.2 [M+H]⁺. HPLC: Purity (254 nm): =100%;t_(R)=9.29 min.

N-(2,3-Dihydro-1H-inden-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (30 mg, 0.16mmol) and 2,3-dihydro-1H-inden-2-amine afforded the title compound (17mg, 35%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ8.10 (d, J=6.4 Hz,1H), 7.92 (s, 1H), 7.26 (dd, J=4.4 Hz, 2.8 Hz, 2H), 7.18 (dd, J=4.4 Hz,2.8 Hz, 2H), 6.46 (d, J=0.8 Hz, 1H), 5.07-5.03 (m, 1H), 3.44 (dd, J=12.4Hz, 4.8 Hz, 2H), 3.00 (dd, J=12.4 Hz, 4.0 Hz, 2H), 2.628 (s, 3H), 2.626(s, 3H). LC-MS m/z: 307.1 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=7.04min.

2,4-Dimethyl-N-(4-(thiazol-4-yl)phenyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.26mmol) and 4-(thiazol-4-yl)aniline afforded the title compound (74.4 mg,81%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ10.32 (s, 1H), 9.19(d, J=2.0 Hz, 1H), 8.49 (s, 1H), 8.09 (d, J=1.5 Hz, 1H), 7.99 (d, J=9.0Hz, 2H), 7.91 (d, J=9.0 Hz, 2H), 6.91 (s, 1H), 2.71 (s, 3H), 2.62 (s,3H). LC-MS m/z: 350.1 [M+H]⁺. HPLC Purity (214 nm): >98%; t_(R)=6.77min.

N-(2,3-Dihydro-1H-inden-4-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure C,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (40 mg, 0.21mmol) and 2,3-dihydro-1H-inden-4-amine afforded the title compound (26.6mg, 40%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ10.16 (s, 1H),8.48 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 6.97 (d,J=7.5 Hz, 1H), 6.92 (s, 1H), 3.03 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz,2H), 2.72 (s, 3H), 2.62 (s, 3H), 2.13 (m, J=7.5 Hz, 2H). LC-MS m/z:307.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.80 min.

2,4-Dimethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (40 mg, 0.21mmol) and 1,2,3,4-tetrahydronaphthalen-1-amine afforded the titlecompound (34.7 mg, 52%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃):δ8.10 (d, J=9.5 Hz, 1H), 7.95 (s, 1H), 7.48 (d, J=6.5 Hz, 1H), 7.18-7.11(m, 3H), 6.47 (s, 1H), 5.59-5.52 (m, 1H), 2.91-2.69 (m, 2H), 2.64 (s,3H), 2.54 (s, 3H), 2.25-2.21 (m, 1H), 1.97-1.92 (m, 3H). LC-MS m/z:321.2 [M+H]⁺. HPLC (214 nm): >99%; t_(R)=7.42 min.

(S)—N-(1-(2-fluorophenyl)ethyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.26mmol) and (S)-1-(2-fluorophenyl)ethanamine afforded the title compound(60 mg, 74%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.66 (d,J=8.0 Hz, 1H), 8.38 (s, 1H), 7.48 (td, J=7.5 Hz, 1.5 Hz, 1H), 7.33-7.28(m, 1H), 7.21-7.16 (m, 2H), 6.82 (s, 1H), 5.41 (m, J=7.5 Hz, 1H), 2.67(s, 3H), 2.53 (s, 3H), 1.52 (d, J=7.0 Hz, 3H). LC-MS m/z: 313.2 [M+H]⁺.LC-MS Purity (214 nm): >99%; t_(R)=8.99 min.

(S)—N-(1-(2-Methoxyphenyl)ethyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.26mmol) and (S)-1-(2-methoxyphenyl)ethanamine afforded the title compound(71 mg, 84%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.68 (d,J=9.0 Hz, 1H), 8.36 (s, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.23 (td, J=9.0 Hz,1.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.91 (t, J=7.5 Hz, 1H), 6.82 (s,1H), 5.41 (m, J=7.5 Hz, 1H), 3.88 (s, 3H), 2.67 (s, 3H), 2.55 (s, 3H)1.45 (d, J=6.5 Hz, 3H). LC-MS m/z: 325.2 [M+H]⁺. LC-MS Purity (214nm): >99%; t_(R)=8.99 min.

(R)—N-(1-(2-Methoxyphenyl)ethyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (35 mg, 0.13mmol) and (R)-1-(2-methoxyphenyl)ethanamine afforded the title compound(55 mg, 65%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.67 (d, J=8.4Hz, 1H), 8.35 (s, 1H), 7.30 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.23 (td, J=8.0Hz, 2.0 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.91 (t, J=7.6 Hz, 1H), 6.82(d, J=0.8 Hz, 1H), 5.41 (m, J=7.2 Hz, 1H), 3.87 (s, 3H), 2.66 (s, 3H),2.54 (s, 3H) 1.43 (d, J=7.2 Hz, 3H). LC-MS m/z: 325.3 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=9.14 min.

(S)—N-(1-(3—Chlorophenyl)ethyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (40 mg, 0.21mmol) and (S)-1-(3-chlorophenyl)ethanamine afforded the title compound(26.5 mg, 39%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.29 (s,1H), 7.47 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.34 (t, J=8.0 Hz, 1H), 7.26(d, J=8.0 Hz, 1H), 6.79 (s, 1H), 5.28 (q, J=7.2 Hz, 1H), 2.72 (s, 3H),2.62 (s, 3H), 1.61 (d, J=6.8 Hz, 3H). LC-MS m/z: 329.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R) =9.49 min.

N-(1-(4-Fluorophenyl)propyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.26mmol) and 1-(4-fluorophenyl)propan-1-amine afforded the title compound(20 mg, 23%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.57 (d,J=8.0 Hz, 1H), 8.37 (s, 1H), 7.42 (td, J=6.0 Hz, 3.0 Hz, 2H), 7.16 (d,J=8.5 Hz, 2H), 6.82 (s, 1H), 4.98 (q, J=6.0 Hz, 1H), 2.67 (s, 3H), 2.53(s, 3H), 1.89-1.83 (m, 2H), 0.90 (t, J=7.5 Hz, 3H). LC-MS m/z: 327.2[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=9.53 min.

N-(1-(5-Fluoro-2-methoxyphenyl)ethyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (40 mg, 0.21mmol) and 1-(5-fluoro-2-methoxyphenyl)ethanamine afforded the titlecompound (22 mg, 31%) as a pale yellow solid. ¹H NMR (500 MHz, MeOD-d₄)δ8.30 (s, 1H), 7.11 (d, J=6.5 Hz, 3.0 Hz, 1H), 7.00-6.97 (m, 2H), 6.81(s, 1H), 5.51 (q, J=7.0 Hz, 1H), 3.93 (s, 3H), 2.73 (s, 3H), 2.65 (s,3H), 1.58 (d, J=7.0 Hz, 3H). LC-MS m/z: 343.2 [M+H]⁺. HPLC: Purity (254nm): >99%; t_(R)=17.13 min

N-(1-(3-Chlorophenyl)propyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.26mmol) and 1-(3-chlorophenyl)propan-1-amine afforded the title compound(32.2 mg, 36%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.31 (s,1H), 7.44 (s, 1H), 7.35-7.33 (m, 2H), 7.28-7.25 (m,1H), 6.82 (s, 1H),5.08 (t, J=7.2 Hz, 1H), 2.73 (s, 3H), 2.64 (s, 3H), 1.97 (m, J=7.6 Hz,1H), 1.02 (t, J=7.2 Hz, 3H). LC-MS m/z: 343.2 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.83 min.

N-(2-(3-Chlorophenyl)propan-2-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (38 mg, 0.20mmol) and 2-(3-chlorophenyl)propan-2-amine afforded the title compound(44.2 mg, 65%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ8.21 (s,1H), 7.92 (s, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.40 (d, J=7.5 Hz, 1H), 7.23(t, J=7.5 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.49 (s, 1H), 2.64 (s, 3H),2.58 (s, 3H), 1.84 (s, 6H). LC-MS m/z: 343.1 [M+H]⁺. HPLC: Purity(214nm): >99%; t_(R)=9.74 min.

(R)—N-(1-(4-Chlorophenyl)ethyl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (50 mg, 0.13mmol) and (R)-1-(4-chlorophenyl)ethanamine afforded the title compound(69 mg, 80%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.53 (d,J=7.0 Hz, 1H), 8.37 (s, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.39 (d, J=8.0 Hz,2H), 6.82 (s, 1H), 5.20-5.14 (m, 1H), 2.67 (s, 3H), 2.52 (s, 3H), 1.50(d, J=7.0 Hz, 3H). LC-MS m/z: 329.2 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=9.40 min.

N-((1R,3R,5S,8R)-3-Butoxybicyclo[3.2.1]octan-8-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (25 mg, 0.13mmol) and (1R,3R,5S)-3-butoxybicyclo[3.2.1]octan-8-amine afforded thetitle compound (18.4 mg, 38%) as a white solid. ¹H NMR (500 MHz,MeOD-d₄) δ8.91 (d, J=7.5 Hz, 1H), 8.33 (s, 1H), 6.83 (s, 1H), 4.20-4.17(m, 1H), 3.59 (t, J=5.0 Hz, 1H), 3.44 (t, J=6.0 Hz, 2H), 2.75 (s, 3H),2.62 (s, 3H), 2.23-2.20 (m, 2H), 2.10-2.06 (m, 4H), 1.95-1.90 (m, 2H),1.85-1.82 (m, 2H), 1.59-1.55 (m, 2H), 1.48-1.44 (m, 0.98 (t, J=7.0 Hz,3H). LC-MS m/z: 371.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=10.92min.

N-((1R,3R,5S,8R)-8-Butoxybicyclo[3.2.1]octan-3-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide&N-((1R,3R,5S,8S)-8-Bbutoxybicyclo[3.2.1]octan-3-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxylic acid (180 mg, 0.94mmol) and (1R,5S,8R)-8-butoxybicyclo[3.2.1]octan-3-amine affordedN-((1R,3R,5S,8R)-8-butoxybicyclo[3.2.1]octan-3-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide(120 mg, 34%) andN-((1R,3R,5S,8S)-8-butoxybicyclo[3.2.1]octan-3-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide(30 mg, 9.0%) as yellow solids.

N-((1R,3R,5S,8R)-8-Butoxybicyclo[3.2.1]octan-3-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide: ¹H NMR (500MHz, MeOD-d₄+D₂O) δ8.28 (s, 1H), 6.82 (d, J=1.0 Hz, 1H), 4.41-4.38 (m,1H), 3.60 (t, J=4.5 Hz, 1H), 3.56 (t, J=6.0 Hz, 2H), 2.73 (s, 3H), 2.62(s, 3H), 2.30-2.27 (m, 2H), 1.89-1.70 (m, 8H), 1.69-1.64 (m, 2H),1.57-1.51 (m, 2H), 1.01 (t, J=7.5 Hz, 3H). LC-MS m/z: 371.2 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=8.52 min.

N-((1R,3R,5S,8S)-8-Bbutoxybicyclo[3.2.1]octan-3-yl)-2,4-dimethylimidazo[1,5-a]pyrimidine-8-carboxamide:¹H NMR (500 MHz, MeOD-d₄) δ8.30 (s, 1H), 6.83 (s, 1H), 4.31 (t, J=7.0Hz, 1H), 3.66 (t, J=4.5 Hz, 1H), 3.54 (t, J=6.5 Hz, 2H), 2.75 (s, 3H),2.62 (s, 3H), 2.40-2.35 (m, 2H), 2.27-2.25 (m, 2H), 2.14-2.11 (m, 2H),1.97-1.88 (m, 2H), 1.70-1.56 (m, 4H), 1.49-1.45 (m, 2H), 0.99 (t, J=6.5Hz, 3H). LC-MS m/z: 371.2 [M+H]⁺. HPLC: Purity (214 nm): 92.10%;t_(R)=8.63 min.

4-Cyclopropyl-N-(5,8-difluoro-4-methylchroman-4-yl)-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (25 mg, 0.10 mmol) and 5,8-difluoro-4-methylchroman-4-amineafforded the title compound (23 mg, 54%) as a yellow solid. ¹H NMR (500MHz, MeOD-d₄): δ8.57 (s, 1H), 7.01 (ddd, J=14.0 Hz, 9.0 Hz, 5.0 Hz, 1H),6.77 (s, 1H), 6.58 (ddd, J=14.0 Hz, 9.0 Hz, 5.0 Hz, 1H), 4.53 (s, 2H),4.45 (ddd, J=11.5 Hz, 5.5 Hz, 4.0 Hz, 1H), 4.92 (td, J=10.5 Hz, 2.0 Hz,1H), 3.47 (s, 1H), 3.24-3.18 (m, 1H), 2.45-2.40 (m, 1H), 2.12 (ddd,J=14.0 Hz, 5.5 Hz, 2.5 Hz, 1H), 1.94 (s, 3H), 1.36-1.33 (m, 2H),1.11-1.07 (m, 2H). LC-MS m/z: 329.2 [M+H]⁺. HPLC Purity (214 nm): 96%;t_(R)=9.59 min.

4-Cyclopropyl-N-(2-(3-(ethoxymethyl)phenyl)propan-2-yl)-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxamide

Following general procedure A,4-cyclopropyl-2-(methoxymethyl)imidazo[1,5-a]pyrimidine-8-carboxylicacid (20 mg, 0.08 mmol) and 2-(3-(ethoxymethyl)phenyl)propan-2-amineafforded the title compound (23 mg, 68%) as a yellow oil. ¹H NMR (500MHz, CDCl₃): δ8.23 (s, 1H), 8.06 (s, 1H), 7.46 (d, J=11.0 Hz, 2H), 7.30(d, J=8.0 Hz, 1H), 7.31 (s, 1H), 7.20 (d, J=7.0 Hz, 1H), 6.67 (s, 1H),4.53 (s, 2H), 4.50 (s, 2H), 3.53 (q, J=7.0 Hz, 2H), 3.45 (s, 3H),2.17-2.13 (m, 1H), 1.88 (s, 6H), 1.32-1.28 (m, 2H), 1.22 (t, J=7.0 Hz,3H), 1.03-0.99 (m, 2H). LC-MS m/z: 422.9 [M+H]⁺. HPLC Purity (214 nm):99%; t_(R)=9.91 min.

Example 37 PREPARATION OF ADDITIONALIMIDAZO[1,5-a]PYRIMIDINE-3-CARBOXAMIDES

Compounds in the table below were also prepared based proceduresdescribed above:

Compound Structure

Example 38 BIOLOGICAL ACTIVITY EVALUATION

The ability of exemplary compounds to activate glucocerebrosidase(Gcase) was measured. Experimental procedures and results are providedbelow.

Part I: Assay Procedure

A 484 μL aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS)(Sigma P7769) in chloroform was evaporated under a stream of nitrogenfor 1 hour. The lipid film was dissolved over 4 minutes of vigorousvortexing in 40 mL of 176 mM K₂HPO₄/50 mM citric acid (pH 4.7)containing 7.5 μL of triton X-100, resulting in a mixed micellarpreparation with a composition of 0.32 mM triton and 0.37 mol % PS.4-Methylumbelliferyl-beta-D-glucopyranoside (ACROS-337025000) wasdissolved in the micellar solution to a final concentration of 2 mM foruse as the reaction substrate.

Test compounds were diluted to the desired concentrations withdimethylsulfoxide (DMSO) from 10 mM stocks, and 0.41 μL of the DMSOcompound mixture was added to 100 μL of micellar solution containing 10nM GCase and 100 nM saposin C (Enzo ALX-201-262-0050). Pre-incubationwas allowed to occur for 30 minutes at room temperature, after which thereaction was initiated by combining 25 μL of substrate solution with 25μL of compound/GCase/saposin mixture. The reaction proceeded for 15minutes at room temperature and was stopped by adding 150 μL of 1Mglycine, pH 12.5. The endpoint of the reaction was monitored bymeasuring fluorescence intensity (excitation: 365 nm; emission: 440 nm)on a SpectraMax i3 instrument (Molecular Devices). Test compounds werescreened at 1.0 and 0.1 μM final concentration, and subsequent 8-pointdose response curves were obtained using 3-fold dilutions from a maximumfinal concentration of 5 μM.

Part II: Results

Gcase activation values for tested compounds are provided in Table 3below, along with cLogP, PSA, and compound solubility in water. Forexperiments in which the test compound was used at a concentration of1.0 μM, the symbol “+” indicates less than 30% Gcase activation; thesymbol “++” indicates Gcase activation in the range of 30% up to 60%;and the symbol “+++”indicates Gcase activation greater than 60%. Forexperiments in which the test compound was used at a concentration of0.1 μM, the symbol “*” indicates less than 10% Gcase activation; thesymbol “**” indicates Gcase activation in the range of 10% up to 20%;and the symbol “***”indicates greater than 20% Gcase activation.

TABLE 3 Compound Solubility in Percent Gcase Activation Compound Water 1μM Test 0.1 μM Test No. Compound Structure cLogP PSA (μg/mL) CompoundCompound III-1 

1.5 57.1 <1.5 +++ ** III-2 

1.7 66.3 5.8 ++ * III-3 

1.3 78.7 4.8 ++ * III-4 

1.3 78.6 7.9 ++ * III-5 

0.7 69.4 26.6 + * III-6 

0.1 81.4 >54.0 + * III-7 

1.7 69.1 0.7 + * III-8 

1.1 81.4 0.4 + * III-9 

1.5 83.4 0.3 + * III-10

1.3 86.2 6.4 + * III-11

1.1 81.4 0.5 + * III-12

1.0 75.5 3.4 + * III-13

1.3 86.2 0.3 + * III-14

0.7 87.9 0.5 + * III-15

0.8 78.6 3.0 + * III-16

1.0 69.1 29.9 + * III-17

1.1 83.4 0.4 + * III-18

0.8 78.6 2.3 + * III-19

1.5 91.0 0.3 ++ * III-20

1.7 90.1 0.3 + * III-21

1.6 69.4 1.1 + * III-22

2.4 57.1 4.7 +++ ** III-23

2.3 78.6 0.3 +++ ** III-24

1.2 86.2 6.0 + * III-25

1.2 89.6 3.8 + * III-26

1.9 78.6 0.5 +++ ** III-27

1.5 78.6 0.2 ++ * III-28

3.0 66.3 0.3 +++ *** III-29

2.0 69.4 0.4 +++ ** III-30

2.1 66.3 0.3 +++ *** III-31

1.3 78.6 <0.01 + * III-32

3.5 57.1 17.2 + * III-33

3.8 75.5 N/A +++ ** III-34

5.0 57.1 24.9 + * III-35

5.1 57.1 21.6 + * III-36

4.7 57.1 11.9 +++ * III-37

4.8 66.3 28.0 ++ * III-38

4.7 57.1 14.9 +++ ** III-39

4.5 57.1 N/A + * III-40

4.5 57.1 40.5 + * III-41

4.2 57.1 7.6 +++ ** III-42

4.2 57.1 18.7 ++ * III-43

4.6 57.1 14.7 +++ ** III-44

4.8 66.3 30.9 ++ * III-45

4.9 57.1 1.0 +++ *** III-46

4.8 66.3 4.9 +++ ** III-47

4.5 66.3 30.6 +++ * III-48

3.4 57.1 N/A +++ ** III-49

2.9 57.1 N/A +++ ** III-50

4.6 75.5 31.3 +++ ** III-51

4.6 75.5 10.5 +++ *** III-52

3.5 84.8 37.6 +++ ** III-53

5.1 84.8 52.9 ++ * III-54

3.0 90.1 23.4 + * III-55

4.1 75.5 26.3 +++ ** III-56

4.1 75.5 14.4 +++ ** III-57

4.6 75.5 38.5 +++ ** III-58

4.6 75.5 28.9 +++ ** III-59

3.8 75.5 26.3 ++ * III-60

4.3 75.5 31.2 + * III-61

4.3 75.5 20.6 ++ * III-62

3.2 66.3 27.0 + * III-63

3.2 66.3 36.2 ++ * III-64

3.4 69.4 0.6 ++ * III-65

4.0 57.1 0.9 +++ ** III-66

3.3 78.6 <0.01 + * III-67

3.2 57.1 18.0 + * III-68

3.6 57.1 21.0 + * III-69

3.7 57.1 16.6 ++ * III-70

3.8 66.3 19.6 ++ ** III-71

4.1 57.1 20.2 ++ * III-72

3.8 75.5 23.6 ++ * III-73

3.8 75.5 31.6 + * III-74

3.6 57.1 37.3 + * III-75

3.4 66.3 22.6 ++ * III-76

3.4 66.3 23.0 ++ * III-77

4.2 57.1 26.0 ++ * III-78

4.2 57.1 39.5 ++ * III-79

3.7 66.3 32.0 ++ * III-80

3.9 66.3 25.9 + * III-81

4.7 57.1 20.3 +++ ** III-82

4.6 57.1 14.8 +++ * III-83

4.2 57.1 16.5 ++ * III-84

4.1 66.3 0.2 +++ *** III-85

4.2 66.3 13.1 +++ * III-86

4.2 663. 14.6 +++ **

Incorporation by Reference

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

Equivalents

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ representsindependently for each occurrence hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxyl, —(C₁₋₄alkylene)-(C₁₋₄alkoxyl), cyclopropyl, cyano, chloro,or fluoro; R² is hydrogen, C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxyl,cyclopropyl, cyano, chloro, or fluoro; R³ represents independently foreach occurrence hydrogen or C₁₋₄alkyl; R⁴ represents independently foreach occurrence hydrogen, C₁₋₄alkyl, or —C(O)R³; X¹ is one of thefollowing: (a) a carbonyl-containing linker selected from —C(O)N(H)-ψ,—C(O)N(H)(C₁₋₆alkylene)-ψ, and —C(O)-(3-6 membered heterocycloalkylenecontaining at least one ring —N(H)— group)-ψ; where ψ is a bond to A¹;or (b) an amine-containing linker selected from —(C₁₋₄alkylene)-N(H)-ψand —(C₁₋₄ alkylene)-N(H)-(C₁₋₄alkylene)-ψ; A¹ is a cyclic groupselected from: C₃₋₁₀ cycloalkyl, phenyl, or 5-6 membered heteroaryl,each of which is substituted by 1 or 2 occurrences of Y¹ and 0, 1, 2, or3 occurrences of Y²; and a bicyclic carbocyclyl that is partiallyunsaturated or a mono-cyclic or bicyclic heterocyclyl, each of which issubstituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3occurrences of Y²; Y¹ represents, independently for each occurrence, oneof the following: 2-8 membered heteroalkyl optionally substituted by a6-10 membered aryl or a 3-10 membered heterocyclyl; 3-10 memberedheterocyclyl, 6-10 membered aryl, C₃₋₇-cycloalkyl, —O—C₃₋₇ cycloalkyl,—O-(3-6 membered heterocyclyl), —O-(6-10 membered aryl), or—O—(C₂₋₆alkynyl); C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 memberedheteroaryl), or C₂₋₆alkenyl; or halogen or cyano; Y² represents,independently for each occurrence, deuterium, C₁₋₆alkyl, C₃₋₆cycloalkyl,halogen, C₁₋₆haloalkyl, C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano,azido, —N(R³)₂, —(C₁₋₆ alkylene)-(5-6 membered heterocyclyl),—(C₁₋₆alkylene)-CO₂R³, or C₁₋₆haloalkyl-substituted C₃₋₆cycloalkyl; andn is 1, 2, or
 3. 2. The compound of claim 1, wherein R¹ representsindependently for each occurrence C₁₋₄ alkyl, C₁₋₄haloalkyl,C₁₋₄alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
 3. The compound ofclaim 1, wherein R¹ is methyl.
 4. The compound of any one of claims 1-3,wherein n is
 2. 5. The compound of claim 4, wherein the R¹ groups arelocated at the 2 and 4 positions of the imidazo[1,5-a]pyrimidinyl. 6.The compound of any one of claims 1-5, wherein R² is hydrogen.
 7. Thecompound of any one of claims 1-6, wherein R³ and R⁴ each representindependently for each occurrence hydrogen, methyl, or ethyl.
 8. Thecompound of any one of claims 1-7, wherein X¹ is —C(O)N(H)-ψ.
 9. Thecompound of any one of claims 1-7, wherein X¹ is—C(O)N(H)(C₁₋₆alkylene)-ψ or —C(O)-(3-6 membered heterocycloalkylenecontaining at least one ring —N(H)— group)-ψ.
 10. The compound of anyone of claims 1-9, wherein A¹ is C₅₋₁₀ cycloalkyl substituted once by Y¹and 0-1 occurrences of Y².
 11. The compound of any one of claims 1-9,wherein A¹ is C₃₋₇-cycloalkyl substituted once by Y¹ and 0-1 occurrencesof Y₂.
 12. The compound of any one of claims 1-9, wherein A¹ is abicyclic carbocyclyl that is partially unsaturated or a bicyclicheterocyclyl, each of which is substituted by 0 or 1 occurrence of Y¹and 0, 1, or 2 occurrences of Y².
 13. The compound of any one of claims1-9, wherein A¹ is phenyl substituted once by Y¹ and 0-1 occurrences ofY².
 14. The compound of any one of claims 1-9, wherein A¹ is a 5-6membered heteroaryl substituted once by Y¹ and 0-1 occurrences of Y².15. The compound of any one of claims 1-9, wherein A¹ is a bicycliccarbocyclyl that is partially unsaturated or a bicyclic heterocyclyl,each of which is substituted by 0 or 1 occurrence of Y² selected fromthe group consisting of C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen,C₁₋₆haloalkyl, hydroxyl, and C₁₋₆alkoxyl.
 16. The compound of any one ofclaims 1-9, wherein A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,or C₁₋₆alkoxyl.
 17. The compound of any one of claims 1-14, wherein anyoccurrence of Y² is independently C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen,C₁₋₆haloalkyl, or hydroxyl.
 18. The compound of any one of claims 1-14,wherein any occurrence of Y² is independently C₁₋₃alkyl.
 19. Thecompound of any one of claim 1-14, 17, or 18, wherein Y¹ is a 2-8membered heteroalkyl optionally substituted by a 6-10 membered aryl or a3-10 membered heterocyclyl.
 20. The compound of any one of claim 1-14,17, or 18, wherein Y¹ is —O—(C₁₋₇ alkyl).
 21. The compound of any one ofclaim 1-14, 17, or 18, wherein Y¹ is —O-butyl, —O-pentyl, or —O-hexyl.22. The compound of any one of claim 1-14, 17, or 18, wherein Y¹ is—(C₁₋₃alkylene)-O-(5-6 membered heteroaryl).
 23. The compound of any oneof claim 1-14, 17, or 18, wherein Y¹ is a 3-10 membered heterocyclyl,6-10 membered aryl, C₃₋₇-cycloalkyl, —O-(3-6 membered heterocyclyl),—O-(6-10 membered aryl), or —O—(C₂₋₆alkenyl).
 24. The compound of anyone of claim 1-14, 17, or 18, wherein Y¹ is a 3-10 membered heterocyclylselected from the group consisting of a 5-6 membered heteroaryl and a5-6 membered heterocycloalkyl.
 25. The compound of any one of claim1-14, 17, or 18, wherein Y¹ is 5-membered heteroaryl.
 26. The compoundof any one of claim 1-14, 17, or 18, wherein Y¹ is furanyl, pyrrolyl,thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
 27. Thecompound of any one of claim 1-14, 17, or 18, wherein Y¹ is C₂₋₆alkynyl,—C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆alkylene)-N(R³)₂,—(C₂₄alkynylene)-(5-6 membered heteroaryl), or C₂₋₆alkenyl.
 28. Thecompound of any one of claim 1-14, 17, or 18, wherein Y¹ is C₂₋₆alkynyl.29. The compound of any one of claim 1-14, 17, or 18, wherein Y¹ is—C≡CH.
 30. The compound of any one of claim 1-14, 17, or 18, wherein Y¹is —C≡C—(C₁₋₆alkylene)-OR⁴.
 31. The compound of any one of claim 1-14,17, or 18, wherein Y¹ is —C≡C—CH₂—O—CH₃.
 32. The compound of claim 1,wherein the compound is represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein: R¹ isindependently methyl, cyclopropyl, isopropyl, or—(C₁₋₄alkylene)-(C₁₋₄alkoxyl); R² is hydrogen; R³ and R⁴ each representindependently for each occurrence hydrogen or C₁₋₄alkyl; A¹ is a cyclicgroup selected from: C₃₋₁₀ cycloalkyl, phenyl, or 5-6 memberedheteroaryl, each of which is substituted by 1 occurrence of Y¹ and 0, 1,or 2 occurrences of Y²; and a bicyclic carbocyclyl that is partiallyunsaturated or a bicyclic heterocyclyl, each of which is substituted by0 or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y²; Y¹ represents,independently for each occurrence, one of the following: 2-8 memberedheteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10membered heterocyclyl; 3-10 membered heterocyclyl, 6-10 membered aryl,—O-(3-6 membered heterocyclyl), —O-(6-10 membered aryl), or—O—(C₂₋₆alkynyl); or C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 memberedheteroaryl), or C₂₋₆alkenyl; Y² represents, independently for eachoccurrence, C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl,C₁₋₆hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, azido, —N(R³)₂,—(C₁₋₆alkylene)-(5-6 membered heterocyclyl), —(C₁₋₆alkylene)-CO₂R³, orC₁₋₆haloalkyl-substituted C₃₋₆ cycloalkyl.
 33. The compound of claim 32,wherein A¹ is C₅₋₁₀ cycloalkyl substituted once by Y¹ and 0-1occurrences of Y².
 34. The compound of claim 32, wherein A¹ is phenylsubstituted once by Y¹ and 0-1 occurrences of Y².
 35. The compound ofany one of claims 32-34, wherein any occurrence of Y² is independentlyC₁₋₃alkyl, halogen, or C₁₋₃haloalkyl.
 36. The compound of any one ofclaims 32-35, wherein Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. 37.The compound of any one of claims 32-35, wherein Y¹ is —O—(C₁₋₇alkyl).38. The compound of any one of claims 32-35, wherein Y¹ is —O-butyl,—O-pentyl, or —O-hexyl.
 39. The compound of any one of claims 32-35,wherein Y¹ is —(C₁₋₃alkylene)-O-(5-6 membered heteroaryl).
 40. Thecompound of any one of claims 32-35, wherein Y¹ is a 5-memberedheteroaryl.
 41. The compound of any one of claims 32-35, wherein Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl.
 42. The compound of any one of claims 32-35, wherein Y¹ ispyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl,pyrazolinyl, or thiazolinyl.
 43. The compound of any one of claims32-35, wherein Y¹ is C₂₋₆alkynyl, —C≡C—(C₁₋₆alkylene)-OR⁴,—C≡C—(C₁₋₆alkylene)-N(R³)₂, —(C₂₋₄alkynylene)-(5-6 membered heteroaryl),or C₂₋₆alkenyl.
 44. The compound of any one of claims 32-35, wherein Y¹is C₂₋₆alkynyl.
 45. The compound of any one of claims 32-35, wherein Y¹is —C≡C—(C₁₋₆alkylene)-O—(C₁₋₂alkyl).
 46. The compound of any one ofclaims 32-35, wherein Y¹ is —C≡C—CH₂—O—CH₃.
 47. The compound of claim32, wherein A¹ is a bicyclic carbocyclyl that is partially unsaturatedor a bicyclic heterocyclyl, each of which is substituted by 0 or 1occurrence of Y¹ and 0, 1, or 2 occurrences of Y².
 48. The compound ofclaim 32, wherein A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl,or C₁₋₆alkoxyl.
 49. The compound of claim 1, wherein the compound is anyone of the compounds in Tables 1, 2, or 3 herein, or a pharmaceuticallyacceptable salt thereof.
 50. A pharmaceutical composition, comprising acompound of any one of claims 1-49 and a pharmaceutically acceptablecarrier.
 51. A method of treating a disorder selected from the groupconsisting of Gaucher disease, Parkinson's disease, Lewy body disease,dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycystic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis, andmultiple myeloma, comprising administering to a patient in need thereofa therapeutically effective amount of a compound of any one of claims1-49 to treat the disorder.
 52. The method of claim 51, wherein thedisorder is Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy.
 53. The method of claim 51,wherein the disorder is Gaucher disease.
 54. The method of claim 51,wherein the disorder is Parkinson's disease.
 55. The method of claim 51,wherein the disorder is Lewy body disease.
 56. The method of claim 51,wherein the disorder is dementia.
 57. The method of claim 51, whereinthe disorder is multiple system atrophy.
 58. The method of any one ofclaims 51-57, wherein the patient is a human.